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Explanation: Due to erectile dysfunction drugs and nitroglycerin discount 5 mg tadalafil mastercard the potentially serious toxicity associated with preparative regimens impotence quitting smoking quality 20mg tadalafil, Clinical Programs must verify that cellular therapy products or suitable donors will be available prior to erectile dysfunction treatment in bangalore order tadalafil 10mg with visa administering preparative regimens erectile dysfunction medication insurance coverage generic 10 mg tadalafil free shipping. There are risks involved in the distribution of cellular therapy products, such as damage to the product container and significant warming events. Ordinarily, cryopreserved cellular therapy products should be chosen, ordered, and transported and/or shipped early enough in the process that the unit(s) will be on-site prior to the start of the preparative regimen. In the event there are problems encountered during transport and/or shipping or discovered upon arrival of the product, the recipient will not be at risk. Cellular therapy products should be assessed to confirm quality and adequacy of dose. Alternatively, Clinical Programs may include a description of a process evident in dictated notes. Explanation: Cellular therapy products obtained from registries or manufacturers outside of the cellular therapy program may differ in important ways for which the Processing Facility must be prepared. Required preparations may include special storage arrangements, necessary supplies and reagents, and developing personnel competency in order to process the product for administration while protecting cell viability and product safety. Explanation: Preparative regimens encompass various modalities, such as biologic, radiologic, and chemotherapy. It is recommended that a tracking system regarding mixture, delivery, and completed administration be instituted for all these regimens. Staff administering the preparative regimen shall be appropriately credentialed as defined by institutional policies and in accordance with governmental laws and regulations. Example(s): Administration of chemotherapy in the preparative regimen context requires specific policy(ies) for safe administration due to the risk of adverse outcomes related to high doses. One formulation must be reconstituted and infused within a 60-minute period; a newer formulation remains stable for five hours (or more if refrigerated). If a Clinical Program begins collaboration on immune effector cell programs with hematologists/oncologists not experienced with cellular therapy, some explanation of the preparative regimen will be necessary. Explanation: It is recognized that treatment orders must be approved by various individuals; however, the height and current weight should be measured and recorded before treatment administration. Explanation: A protocol or standard of care-specific set of orders that are preprinted and readily available in written or electronic form is an important measure of control; however, it is still critical that the drug doses are verified and documented by an attending physician prior to transmitting the order to the pharmacy. A final checklist is required to confirm each step in preparing for and administering therapy is performed prior to cellular therapy product administration. Written instructions should be available for reconstitution, dilution, mixing, labeling, and packaging. There should be a standard process in place to retrieve the batch number and expiry of all drugs and diluents used in the preparation of the therapy regimens. Evidence: Copies of standard treatment or research protocols in areas of recipient care such as inpatient and outpatient units and the pharmacy can provide evidence of compliance. Specific patient charts can be used to check that treatment orders and documentation are compliant with the guidelines. While touring patient care areas, the inspector may also ask the pharmacists about their normal practice and if they retain ultimate responsibility for verification against the protocol or standard regimen listed on the orders. Nurses may be asked about the normal procedures for treatment administration to confirm this. Explanation: In writing as used in the Standards includes electronic documentation. Information from the radiation oncology consultation, including factors that may increase the toxicity of the radiation, should be discussed with the patient and informed consent should be documented. Documentation that the radiation was given on a specific date and its dose can be compared to the consultation documentation. The inspector can also ask to see copies of treatment protocols that include radiation and verify the protocol by comparing it to patient charts. Explanation: Non-cryopreserved (often referred to as fresh?) cellular therapy products must be administered within the time specified by Clinical Program policies, registry and tissue bank requirements, and applicable laws and regulations. It may be optimal to thaw individual bags to reduce the time thawed products sit before administration. Clinical Programs must identify appropriate timeframes between the end of the preparative regimen and administration of the cellular therapy product to confirm that the administered product is not affected by the preparative regimen. The program must verify that the preparative regimens were given at the scheduled time and delay administration of the cells if required. Programs are responsible for communicating with the Processing Facility regarding any delayed administration. Clinical Programs need to determine the composition of the cellular therapy product to determine how it should be prepared for administration. Programs should work with their Processing Facilities to verify appropriate processing and preparation of the product for administration. Evidence: Staff should be prepared to discuss their normal practice and their training in the administration of cellular therapy products. Specific patient charts can be used to determine that two persons checked the product and that the documentation in the chart is complete. If there is time and an administration is scheduled on the day of inspection, the inspector should be notified so that he/she may watch parts of the procedure. One way Clinical Programs can communicate date and time of administration to the Processing Facility is to use a facesheet or other written documentation of the start and end date of the preparative regimen and the date and time, if needed, of the cellular therapy product administration. If plans change, updated information is provided to the laboratory prior to the planned day of administration. Monitoring of vital signs is generally part of routine hospital policy for blood products; however, given the potential for administration reactions. Management might include back-up plans such as an alternative donor, repeating a collection procedure, or performing an emergency marrow collection. Clinicians must consult with the Processing Facility to make clinical decisions based on methods of cellular therapy product preparation. Explanation: In the case of transplants using more than one cellular therapy product. Example(s): For double cord blood transplants, preferably the second unit should not be thawed until administration of the first unit is completed and the Clinical Program is reasonably certain that no adverse reactions are occurring. Example(s): the inter-organizational Circular of Information for the Use of Cellular Therapy Products may be used to fulfill this requirement. Clinical Programs are expected to have a system in place to monitor for these complications and provide appropriate courses of action if they occur. Explanation: Discharges should normally take place after recipients have achieved clinical and hematological stability. A Clinical Program may adopt a policy of discharging recipients before they have achieved clinical and hematological stability, with ongoing inpatient care undertaken by another clinical unit. Equally, a program may adopt a policy of post-transplant care to be delivered in local and regional facilities. These patients must receive care according to established guidelines and with documented oversight of the cellular therapy program. Evidence: the working relationships between the Clinical Program and receiving unit should be clearly documented, including explicit criteria for transfer back to the transplant center. Inspectors will determine how and if the Clinical Program adequately evaluates that receiving facilities are adequate for post-transplant care and have the right to arrange direct inspection of receiving facilities to confirm compliance with the Standards. Example(s): A shared care arrangement may be justified by a balance of clinical, economical, and geographical factors that clearly benefit overall patient care without compromising safety. When not performed within the program itself, written agreements must require compliance with the Standards. The inspector is not required to review records on site if the facility is external. This will depend on the therapy plan; for example, depending on the length of the therapy regimen, reports may be created after every procedure, monthly, etc. Das-Gupta E, Dignan F, Shaw B, Raj K, Malladi R, Gennery A, Bonney D, Taylor P, Scarisbrick J. For those programs referring patients to external facilities, written agreements should require that the facilities follow a written procedure including a written informed consent. Attending physicians may want to request additional laboratory testing, such as Creactive protein, lactate dehydrogenase, ferritin, and fibrinogen. While there are different forms of immune effector cellular therapy being used, they share important immune-related features that Clinical Programs should be cognizant of and be prepared to manage. Long-term follow-up is essential for detecting and managing late effects of cellular therapy and it requires expertise that is different from that for acute care of recipients. Late effects may include endocrine and reproductive function (new onset diabetes, thyroid dysfunction, hypogonadism), osteoporosis, cardiovascular risk factors (hypertension, dyslipidemia, metabolic syndrome, lifestyle factors), respiratory function, chronic renal impairment and secondary cancers.

The instructions for 113 mustard gas were incomplete and insufficient for actual production of the agent impotence versus erectile dysfunction purchase 2.5 mg tadalafil mastercard. In the case of cyanide erectile dysfunction 42 20 mg tadalafil with visa, the instructions did not indicate that the precursor chemicals were 114 difficult to how does an erectile dysfunction pump work buy cheap tadalafil 20mg on line procure impotence def buy tadalafil online pills. The process outlined for botulinum toxin was very difficult to 115 master and likely would not have resulted in the successful production of the agent. The instructions for plague bacteria were rudimentary and did not indicate that it would be difficult to find a suitable host to extract a culture, or that the plague is fragile and is 116 very difficult to weaponize and disperse effectively. Primarily, the author borrowed text and sketches from the 1977 American biology book Microbiology by Michael J. As for the various postings dealing with nuclear or radiological weapons, one is mainly informational and appears to be a translation of a document written by Outlaw 118 Labs, which is currently posted on various American websites. It does, however, outline the expected economic damage of such an attack and 119 lists possible Western cities as targets. A third posting detailing instructions for enrichment of uranium and the manufacture of an atom bomb was ludicrous. The instructions borrowed from a fringe publication in English were simply sub-par and absent of any real scientific expertise. They coach the would-be terrorist not to be fearful of working with nuclear fissile material, for radiation is actually good for us. Furthermore, these instructions teach a would-be terrorist how to enrich uranium on a kitchen table by using commercial grade uranium metal, 120 hydrofluoric acid, a few buckets, and a bicycle pump. Enriching uranium is a technologically formidable task that is beyond the modest scientific means of a transnational terror network with access to commercial grade uranium, bicycle pumps, and kitchen tables. The most serious al-Qaeda-related nuclear text, the Nuclear Preparation Encyclopedia, was posted in October 2005 on the jihadi website al-Firdaws. As mentioned previously, it is a multi-chapter collection that was compiled and written by a selfdescribed supporter of al-Qaeda, Layth al-Islam (the Lion of Islam). Unlike previous literature that was largely void of scientific data, this document contains tens of pages on a historical survey of nuclear technology, including an Arabic explanation of nuclear experiments, concepts, and an overview of Enrico Fermi as well as other prominent nuclear pioneers. Most disturbing, it includes information about critical mass and the amount of fissile materials needed in the construction of nuclear weapons. In addition, various sketches and diagrams in English and Arabic are provided of purported gun-type and implosion-type nuclear warheads, which are clearly borrowed from open-source 121 information available on the Internet. The author claims, I have been studying nuclear physics for two years on various scientific and Jihadi websites and that his posting is a present to the Amir [captain] of the Mujahideen Sheikh Osama bin Laden, God bless him, for the Jihad in the path of 122 god. Khan network), it is noteworthy as it reveals an increase in the understanding of nuclear technology by the jihadi community. The author details steps for the extraction of the radioactive material radium and the assembly of a gun-type radium bomb, which he inaccurately claims can yield a nuclear explosion. Not only are there basic technical flaws in these instructions, but the literature also fails to mention the importance of effective deployment strategies and techniques. Raymond Zilinskas, co-editor of the Encyclopedia of Bioterrorism Defense: Acquiring an effective biological weapon and carrying out a successful biological attack requires the criminal to take four vital steps: (1) secure a culture of a suitable pathogen or a quantity of toxin; (2) develop an appropriate formulation*that is, a combination of the pathogen or toxin and the substrate in which it is suspended or dissolved; (3) obtain an appropriate container to store safely and transport the formulations; and (4) apply an efficient mechanism to disperse the pathogen or toxin over or onto the target population. At a most basic level, a terrorist cell needs the proper technical expertise in order to weaponize and deliver the agent to its target. This involves ensuring the chemical stability of the agent during the filling of munitions. Moreover, there are no specific instructions on how to manufacture or utilize credible dispersal methods. Finally, al-Qaeda literature does not contain any detailed information on the impact of atmospheric conditions. A posting on an al-Qaeda website informs a Mujahid how to purchase and deploy cyanide: Go to a place that sells poisons and ask about cyanide, which is very affordable. Then purchase some hand lotion at a supermarket specifically the kind that opens pores. Take a teaspoon of cyanide and add some of the hand lotion and mix it well very carefully. They state, Following the successful experiments put the poison in a glass container and watch out specifically for cars of Americans and other enemies, and apply some of the poison on the door handle. This should not be done in a clumsy way, but you should use a piece of cotton to properly apply. Observe him well and make sure that you are close to him especially to his shopping cart. Proclamations of weapons of mass destruction possession also increase the stature and the apparent capability of the al-Qaeda movement. Libya is a prime example of the inherent difficulty of manufacturing and weaponizing such agents. Libya had a scientific cadre of 120 chemical, 132 800 nuclear, and 4,000 missile specialists. Yet the net result of this largely uninterrupted lavish effort was rather unimpressive. This is a noteworthy fact, especially considering the enormous attention garnered by the anthrax cases in 2001. A 2003 report for the Pentagon estimated that if terrorists released a large amount of anthrax bacteria in a large city under optimal weather conditions, it would infect 200,000 people in an area 40 133 miles downwind. These hurdles can only be overcome if and when the al-Qaeda movement acquires such scientific capability that fortunately still appears beyond its means. Difficulties in Deployment the Case of Aum Shinrikyo A In March 1995, the Japanese cult Aum Shinrikyo released sarin gas in the Tokyo subway 134 system, killing 12 people and injuring more than 1,000. Cultists spread the sarin solution by puncturing small bags containing the agent with sharpened umbrella tips. One Aum member was placed on each of five subway cars converging on the Kasumigaseki station during morning rush hour. The incident was the culmination of years of secretive research and development efforts to produce biological and chemical agents as terrorist weapons. Although the subway attacks resulted in a loss of human life and led to widespread panic throughout Tokyo, the incident could have had far deadlier repercussions had the agent been weaponized and disseminated using more advanced techniques. Japanese authorities believe that by 1995, the cult had produced both botulinum toxin and anthrax bacteria. Aum scientists were also able to acquire advanced laboratory materials, including filtration systems, electron microscopes, sophisticated 137 computer systems, and documents describing the intricacies of agent cultivation. The cult obtained this specialized equipment through complex procurement networks and actually acquired many precursor chemicals through legal channels in the pharmaceutical 138 industry. Aum Shinrikyo allegedly conducted at least 20 attacks utilizing chemical and biological agents between 1990 and 1995; however, few of these attacks resulted in any 139 casualties. Only 20 individuals were killed as a result of these 20 attacks, spread across five years. Another failed attack occurred in early March 1995, as the cult attempted to spread what they believed was botulinum toxin in the Tokyo 141 subway but was unable to properly disseminate the agent. Despite the ease of acquisition of precursor materials and equipment, the high level of technical expertise among group members, and the relatively long periods of time that the group was able to operate in secret without police intervention, the cult was still unable to carry out a single true mass-casualty attack. Al-Qaeda appears to be far less organized than the Aum Shinrikyo cult had been before the March 1995 sarin attacks in Tokyo. Additionally, there is no evidence to suggest that the al-Qaeda network has had access to the kinds of sophisticated technology or expertise enjoyed by Aum cultists in the 1990s. Indeed, instances of attempted acquisition of radiological materials by al-Qaeda affiliates have occurred. In addition, these casualties would likely be caused by 142 the explosion itself, rather than by the effects of radiation. The most dangerous scenario would be direct inhalation or ingestion of a radiological substance. For one, a group would have to acquire a radioactive isotope with a relatively short half-life in order to ensure maximum radiation. Indeed, it is probable that only those individuals who are close enough to the device to risk sustained injuries or death from the explosion would receive lethal doses of radiation. In addition, it is likely that individuals near an explosion would move quickly from the area, thus drastically reducing the chance of radiation sickness. These individuals may experience burns on the skin or changes in the number of white blood cells, but would likely avoid more severe reactions. The only scenarios which could generate high numbers of fatalities under the right circumstances would be direct exposure to radioactive material emitting gamma rays, or injuries sustained from an explosion involving radioactive 145 shrapnel. Although many sources of radioactive isotopes exist, numerous obstacles can prevent terrorist acquisition.

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When testing for environmental chemical that minor variations in cooler temperature contaminants and pesticides is used as the measurements can be avoided by control measure erectile dysfunction 16 purchase tadalafil 5mg on line, it is now recommended submerging the sensor for the temperaturethat the adequacy of the testing methods recording device in a liquid that mimics the and equipment be verifed periodically erectile dysfunction causes infertility order 2.5 mg tadalafil otc. However impotence mayo cheap tadalafil 2.5 mg without prescription, there may be circumstances where parahaemolyticus erectile dysfunction treatment by exercise trusted tadalafil 5 mg, and Vibrio cholarae this approach is suitable. It is also noted non-O1 and non-0139 are generally that minor variations in cooler temperature associated with marine and estuarine species measurements can be avoided by of fsh and may not be reasonably likely to submerging the sensor for the temperatureoccur in freshwater species or non-fshery recording device in a liquid that mimics the ingredients, unless they have been crosscharacteristics of the product; contaminated;. It is now clarifed that products that are internal temperature of the fshery product partially cooked to set the batter or breading is checked at receipt, because the transit or stabilize the product shape. A control strategy pasteurization process is now recommended: to ensure that refrigerated dried products are a minimum cumulative total lethality of F194?F properly labeled when refrigeration is the sole (F90?C) = 57 minutes, where z = 15. Information concerning levels of Listeria are properly labeled when freezing is the sole monocytogenes (L. At present, the chapter applies recommended for monitoring temperatures exclusively to the processing of molluscan in processing areas. However, the recommendations in Chapter 16 for the these technologies may have other applications control of pathogenic bacteria survival through as well. It now contains a table of Japanese and Hawaiian vernacular names and their corresponding U. It now contains information regarding the public health impacts of bacterial and viral pathogens of greatest concern in seafood processing. The codifed portion of the Or you may download a copy from: regulations is included in Appendix 8. Note that this is a twoor have conducted for them, a hazard analysis page form, with the second page to be used if to determine whether there are food safety your process has more critical control points than hazards that are reasonably likely to occur in can be listed on one page. A blank Hazard Analysis and fshery products that you process if there are Worksheet is contained in Appendix 1. Note that signifcant food safety hazards associated with the this is also a two-page form, with the second page products. The regulation does not require that you to be used if your process has more processing use the form included in Appendix 1. The purpose of the diagram is to provide a Identify how the product is distributed and stored clear, simple description of the steps involved in after distribution. The fow diagram should be on the frst page of both the Hazard Analysis verifed on-site for accuracy. Biological, chemical, and physical hazards can Identify the intended consumer or user of the affect the safety of fshery products. The intended consumer may be the safety hazards are associated with the product general public or a particular segment of the. The fsh is raised or caught, and the region of the intended user may also be another processor that world from which the fsh originates). These hazards are introduced within the Record this information in the space provided processing plant environment. This guidance on the frst page of both the Hazard Analysis refers to these as process-related hazards. Use Table 3-2 for vertebrates more than one fnished product food category (animals with backbones) such as fnfsh. Use from Table 3-4, which will happen when your Table 3-3 for invertebrates (animals without product fts more than one description. For backbones) such as shrimp, oysters, crabs, and example, if you cook shrimp and use it to prepare lobsters. Determine whether the species has a a fnished product salad, you should look at both potential species-related hazard by looking for the cooked shrimp and the salads prepared a v mark (or oneor three-letter codes for a from ready-to-eat fshery products categories in natural toxin) in the right-hand columns of the Table 3-4, Column 1. If it does, record the potential speciesfnished product food categories apply to your related hazard(s) in Column 2 of the Hazard product and should be listed in Column 2 of the Analysis Worksheet, at every processing step. You your own expertise, or that of outside experts, as should use your own expertise, or that of outside necessary, to identify any hazards that may not experts as necessary, to identify any hazards be included in the table. You may already that are new or unique to your physical plant, have effective controls in place for a number of equipment, or process). Consult the hazards and controls chapters of the likelihood of a hazard occurring should be this guidance document (Chapters 4 through 7, judged in the absence of controls. For example, the 9, and 11 through 21) for each of the potential fact that scombrotoxin (histamine) development hazards that you entered in Column 2 of the in a particular species of fsh has not been noted Hazard Analysis Worksheet. Each chapter that are already in place to prevent its development contains a section, Understand the Potential. Hazard, that provides information about the In the frst case, the hazard is not reasonably signifcance of the hazard, the conditions under likely to occur. In the second case, the hazard is which it may develop in a fshery product, and reasonably likely to occur, and the controls should methods available to control the hazard. Narrow the list of potential hazards that you Find in Table 3-4 (Chapter 3) the fnished product entered in Column 2 of the Hazard Analysis food (Column 1) and package type (Column 2) Worksheet to those that are signifcant or, in that most closely match the information that you other words, reasonably likely to occur. You should the hazards and controls chapters of this evaluate the signifcance of a potential hazard guidance (Chapters 4 through 7, 9, and 11 independently at each processing step. It may through 21) each contain a section, Identify be signifcant at one step but not at another. Each chapter discusses one or more the hazard can be introduced at an unsafe level control strategy example(s) for how the hazard at that processing step; or (2) it is reasonably can be controlled, because there are often more likely that the hazard can increase to an unsafe ways than one to control a hazard. When evaluating the signifcance Column 5 of the Hazard Analysis Worksheet for of a hazard at a processing step, you should each Yes answer in Column 3. This information can cooker and the speed of the belt that carries the be found in Column 2 of the Hazard Analysis product through the cooker (because you have Worksheet. These steps involve setting time), you should specify water temperature critical limits, establishing monitoring procedures, and belt speed as critical limits, not the internal establishing corrective action procedures, temperature of the product. The hazards and controls chapters control strategy example provided in the hazards of this guidance document (Chapters 4 through and controls chapters of this guidance (Chapters 7, 9, and 11 through 21) each contain a section, 4 through 7, 9, and 11 through 21) each contain Establish Monitoring Procedures, that provides a section, Set Critical Limits, that provides information about appropriate monitoring information about appropriate critical limits for procedures for each of the control strategy each of the control strategy example(s) discussed. You should set a critical limit at such a value that To fully describe your monitoring program, you if it is not met, the safety of the product may be should answer four questions: (1) What will be questionable. On the other hand, if you set a critical It is important for you to keep in mind that the limit that is too loose, you could, as a result, monitoring process should directly measure allow an unsafe product to reach the consumer. The necessary frequency of to set an operating limit that is more restrictive monitoring is dependent upon the circumstances. In this way, you can adjust Continuous monitoring is always desirable, and the process when the operating limit is not in some cases necessary. This Corrective Action Procedures, that provides is especially true if these values are typically information about appropriate corrective action close to the critical limit. Additionally, the greater procedures for each of the control strategy the time span between measurements, the example(s) discussed. Even with continuous If the corrective action involves testing the monitoring, the paper or electronic record of the fnished product, the limitations of the sampling continuous monitoring should be periodically plan should be understood. Because of these checked in order to determine whether limitations, microbiological testing is often not a deviations from the critical limit have occurred. However, a predetermined corrective information about appropriate records for each action has the following advantages: (1) It of the control strategy example(s) discussed. The hazards and controls chapters of this guidance (Chapters 4 through 7, 9, and 11 through 21) each contain a section, Establish Verifcation Procedures, that provides information about appropriate verifcation activities for each of the control strategy example(s) discussed. However, it can be a useful tool, especially when coupled with a relatively weak monitoring procedure, such as reliance upon suppliers certifcates. Purpose provided in Chapters 4 through 21, and your the purpose of this chapter is to identify own expertise or that of outside experts, to potential food safety hazards that are species determine whether the hazard is signifcant related and process related. It also provides for your particular product and, if so, how it information on how the illicit substitution of should be controlled. Table 3-2, Potential Vertebrate substitution may cause potential food safety Species-Related Hazards, contains a hazards to be overlooked or misidentifed by list of potential hazards that are associated processors or end users, as shown in Table with specifc species of vertebrates 3-1, The Effect of Misbranding Through (species with backbones). These hazards Species Substitution on the Identifcation of are referred to as species-related hazards; Potential Species-Related Hazards. Table 3-4, Potential Process-Related Hazards, contains a list of potential hazards that are associated with specifc fnished fshery products, as a result of the fnished product form, the package type, and the method of distribution and storage. Indicates that the ciguatera hazard is associated with this species only in the tropical Pacifc Ocean. This hazard applies where the processor has knowledge or has reason to know that the parasite-containing fsh or fshery product will be consumed without a process suffcient to kill the parasites, or where the processor represents, labels, or intends for the product to be so consumed. This hazard, when caused by consuming infected feed, only applies if fsh processing waste, fresh fsh, or plankton is used as feed.

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Other tests that require days for results include stool culture for Campylobacter jejuni as a precipitant of Guillain-Barre syndrome and assays for the autoantibodies that cause myasthenia gravis erectile dysfunction and stress discount tadalafil online amex, Lambert-Eaton syndrome impotence 40 years cheap tadalafil line, and Guillain-Barre syndrome xeloda impotence order 5mg tadalafil amex. Foods suspected of being contaminated should be refrigerated until retrieval by public health personnel erectile dysfunction drugs causing buy tadalafil 5 mg cheap. In the United States, the percentage of persons who died of foodborne botulism decreased from 25% 42 during 1950-1959 to 6% during 1990-1996, with a similar reduction for each botulinum toxin type. Despite this increase in survival, the paralysis of botulism can persist for weeks to months with concurrent requirements for fluid and nutritional support, assisted ventilation, and treatment of complications. Therapy for botulism consists of supportive care and passive immunization with equine antitoxin. Timely administration of passive neutralizing antibody will minimize subsequent nerve damage and severity of disease but will 81, 82 not reverse existent paralysis. Antitoxin should be given to patients with neurologic signs of 47 botulism as soon as possible after clinical diagnosis. Antitoxin may be withheld at the time of diagnosis if it is certain that the patient is improving from maximal paralysis. The licensed trivalent antitoxin contains neutralizing antibodies against botulinum toxin types A, B, and E, the most common causes of human botulism. However, the time required for correct toxin typing and subsequent administration of heptavalent antitoxin would decrease the utility of this product in an outbreak. The dose and safety precautions for equine botulinum antitoxin have changed over time. Clinicians should review the package insert with public health authorities before using antitoxin. At present, the dose of licensed botulinum antitoxin is a single 10-mL vial per patient, diluted 1:10 in 0. The amount of neutralizing antibody in both the licensed and the investigational equine antitoxins far exceeds the highest serum toxin levels found in foodborne botulism patients, and additional doses are usually not required. If a patient has been exposed to an unnaturally large amount of botulinum toxin as a biological weapon, the adequacy of neutralization by antitoxin can be confirmed by retesting serum for toxin after treatment. From 1967 to 1977, when the recommended dose was larger than today, approximately 9% of recipients of equine botulinum antitoxin in the United States displayed urticaria, serum sickness, or other reactions suggestive of 84 hypersensitivity. Anaphylaxis occurred within 10 minutes of receiving antitoxin in 2% of recipients. To screen for hypersensitivity, patients are given small challenge doses of equine antitoxin before receiving a full dose. Patients responding to challenge with a substantial wheal and flare may be desensitized over 3 to 4 hours before additional antitoxin is given. During the infusion of antitoxin, diphenhydramine and epinephrine should be on hand for rapid administration in case of adverse reaction. Although both equine antitoxins have been partially despeciated by enzymatic cleavage of the allogenic Fc region, each contains a small residual of intact antibody that may sensitize recipients to additional doses. Botulism patients require supportive care that often includes feeding by enteral tube or parenteral nutrition, intensive care, mechanical ventilation, and treatment of secondary infections. Patients with suspected botulism should be closely monitored for impending respiratory failure. In nonventilated infants with botulism, a reverse Trendelenburg positioning with cervical vertebral support has been helpful, but applicability of this positioning to adults with botulism remains untested. This tilted, flatbody positioning with neck support may improve ventilation by reducing entry of oral secretions into the airway and by suspending more of the weight of the abdominal viscera from the diaphragm, thereby improving respiratory excursion (Figure 4). In contrast, placing a botulism patient in a supine or semirecumbent position (trunk flexed 45 at the waist) may impede respiratory excursion and airway clearance, especially if the patient is obese. Botulism patients should be assessed for adequacy of gag and cough reflexes, control of oropharyngeal secretions, oxygen saturation, vital capacity, and inspiratory force. When respiratory function deteriorates, controlled, anticipatory intubation is indicated. The proportion of patients with botulism who require 64 mechanical ventilation has varied from 20% in a foodborne outbreak to more than 60% in infant 85 botulism. In a large outbreak of botulism, the need for mechanical ventilators, critical care beds, and skilled personnel might quickly exceed local capacity and persist for weeks or months. Development of 86 a reserve stockpile of mechanical ventilators in the United States is under way and will require a complement of staff trained in their use. However, secondary infections acquired during botulism often require antibiotic therapy. Aminoglycoside antibiotics and clindamycin are 87, 88 contraindicated because of their ability to exacerbate neuromuscular blockade. Standard 89 treatments for detoxification, such as activated charcoal, may be given before antitoxin becomes available, but there are no data regarding their effectiveness in human botulism. Despite the risks of 43, 90 immediate hypersensitivity and sensitization to equine proteins, both children and pregnant 91, 92 women have received equine antitoxin without apparent short-term adverse effects. Treatment with human-derived neutralizing antibody would decrease the risk of allergic reactions posed by equine botulinum antitoxin, but use of the investigational product, Botulism Immune Globulin Intravenous (Human) (California Department of 82, 93 Health Services, Berkeley), is limited to suspected cases of infant botulism. Passive immunity can be provided by equine botulinum antitoxin or by specific human hyperimmune globulin, while endogenous immunity can be induced by immunization with botulinum toxoid. Use of antitoxin for postexposure prophylaxis is limited by its scarcity and its reactogenicity. Because of the risks of equine antitoxin therapy, it is less certain how best to care for persons who may have been exposed to botulinum toxin but who are not yet ill. In a small study of primates exposed to aerosolized toxin in which supportive care was not provided, all 7 monkeys given antitoxin after exposure but before the appearance of neurologic signs survived, while 2 of 4 monkeys treated with 39 antitoxin only after the appearance of neurologic signs died. Moreover, all monkeys infused with neutralizing antibody before exposure to toxin displayed no signs of botulism. In a balance between avoiding the potential adverse effects of equine antitoxin and needing to rapidly neutralize toxin, it is current practice in foodborne botulism outbreaks to closely monitor persons who may have been 47 exposed to botulinum toxin and to treat them promptly with antitoxin at the first signs of illness. To facilitate distribution of scarce antitoxin following the intentional use of botulinum toxin, asymptomatic persons who are believed to have been exposed should remain under close medical observation and, if feasible, near critical care services. The pentavalent toxoid has been used for more than 30 years to immunize more than 3000 laboratory workers in many countries. Immunization of the population with botulinum toxoid could in theory eliminate the hazard posed by botulinum toxins A through E. However, mass immunization is neither feasible nor desirable for reasons that include scarcity of the toxoid, rarity of natural disease, and elimination of the potential therapeutic benefits of medicinal botulinum toxin. Accordingly, preexposure immunization currently is neither recommended for nor available to the general population. Botulinum toxoid induces immunity over several months and, so, is ineffective as postexposure prophylaxis. Heating to an internal temperature of 52 85?C for at least 5 minutes will detoxify contaminated food or drink. All foods suspected of contamination should be promptly removed from potential consumers and submitted to public health authorities for testing. Persistence of aerosolized botulinum toxin at a site of deliberate release is determined by atmospheric conditions and the particle size of the aerosol. Extremes of temperature and humidity will degrade the toxin, while fine aerosols will eventually dissipate into the atmosphere. Depending on the weather, 96 aerosolized toxin has been estimated to decay at between less than 1% to 4% per minute. At a decay rate of 1% per minute, substantial inactivation (13 logs) of toxin occurs by 2 days after aerosolization. Recognition of a covert release of finely aerosolized botulinum toxin would probably occur too late to prevent additional exposures. When exposure is anticipated, some protection may be conferred by 97 covering the mouth and nose with clothing such as an undershirt, shirt, scarf, or handkerchief. Patients with suspected botulism do not need to be isolated, but those with flaccid paralysis from suspected meningitis require droplet precautions. Rapid diagnostic and toxin typing techniques currently under development would be useful for recognizing and responding to a bioterrorist attack.

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