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Summary purchase disulfiram 500 mg line, Evidence Report/ vation and validation of the Glasgow alcoholic hepatitis score discount 250mg disulfiram free shipping. The long- Model for end stage liver disease score predicts mortality across a broad term cost-effectiveness of improving alcohol abstinence with adjuvant spectrum of liver disease discount disulfiram 500 mg amex. Expert prognostic model than Child-Turcotte-Pugh score or Discriminant Opin Pharmacother 2005;6:2103-2115. New concepts of the pathogenesis of alcoholic liver disease non-cirrhotic patients. Science Five-year survival predictive factors in patients with excessive alcohol 1982;217:169-175. Studies in alcoholic liver Administration Cooperative Study Group on Alcoholic Hepatitis. Duration of survival in patients with Laennec’s duced hepatitis treated with steroids or enteral nutrition: a multicenter cirrhosis. Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, et quantitative evaluation and optimal timing. Orthotopic liver transplantation for alcoholic liver disease: a retrospective 201. Treatment analysis of survival, recidivism, and risk factors predisposing to recidi- of alcoholic hepatitis. Predictive factors of alcohol relapse after orthotopic liver Med 1990;113:299-307. The role of the tis–a Cochrane Hepato-Biliary Group systematic review with meta-anal- discriminant factor in the assessment and treatment of alcoholic hepatitis. Severe alcoholic hepatitis with extremely high neutrophil count hepatitis–a randomised clinical trial. Long-term oral branched-chain amino acid treatment in chronic he- calorie malnutrition to alcoholic liver disease: a reexamination of data paticencephalopathy. Controlled trial on nutrition supplementation in outpatients with symp- TheLillemodel:anewtoolfortherapeuticstrategyinpatientswithsevere tomatic alcoholic cirrhosis. Am J Clin fylline improves short-term survival in severe acute alcoholic hepatitis: a Nutr 1982;35:56-72. Recent Dev Alcohol 1984;2:135- randomized, double-blinded, placebo-controlled multicenter trial of Et- 141. S-adenosyl-L-methionine: its role in the treatment of liver Early switch to pentoxifylline in patients with severe alcoholic hepatitis is disorders. A randomized, controlled trial of treatment of alcoholic hepatitis with 1999;30:1081-1089. S-adenosyl-L-methionine for alcoholic liver dis- and impact of disease recurrence. Colchicine treatment of alcoholic cirrhosis: a randomized, placebo- rent management and outcomes. Adiponectin, a new member of the family of soluble defense collagens, ural history and evaluation of prednisolone therapy. Ann Intern Med negatively regulates the growth of myelomonocytic progenitors and the 1971;74:311-321. Randomized controlled trial of silymarin treatment in patients with cir- With a note on published results in encephalopathic patients. Double-blind and/orhepatitisBorCliverdiseases–asystematiccochranehepato-biliary controlled trial of prednisolone therapy in patients with severe acute group review with meta-analyses of randomized clinical trials. Liver transplantation alcohol related liver disease: (deliber- ately) stirring a hornet’s nest! Short-term and long-term survival in patients with alco- Minimal criteria for placement of adults on the liver transplant waiting holic hepatitis treated with oxandrolone and prednisolone. N Engl J Med list: a report of a national conference organized by the American Society 1984;311:1464-1470. Infected cat- best approach to prevention is sur- develop on the feet and teats of ani- tle are depressed, reluctant to move, veillance. It is spread not able to eat which can lead to a Becoming aware of the signs of the by direct contact with infected ani- decrease in milk production. They disease (sores in the mouth, on the mals, through the air, and on con- also drool, and in many cases, make feet, teats) and the conditions result- taminated objects. It can also be spread when healthy animals eat (oral) from a feed trough where an infected animal has eaten or drooled saliva. Strict biosecurity practices can help you - Stay off this farm unless given permission to enter. Use strict biosecurity measures for animals, ani- - All visitors should be accompanied by some- mal products, vehicles, people and equipment. Restrict or stop all animal movement to pre- - Accurate record keeping of traffc on your vent entry or spread of the disease. This Employees will minimize the chance of the disease being introduced onto your farm. Vehicles - Change gloves, clothes, hats and wash and disinfect boots between farms. Wildlife and Other Animals (See Appendix E) Animals • Prevent contact with free roam- ing animals (wildlife, cats, dogs). Bovine Alliance on Management and Nutri- • Visitors must remove and leave be- tion. Handling foreign animal diseases hind protective outer clothing and foot- in cattle. Accessed on • Anyone allowed in animal areas should be re- July 06, 2005 at http://www. Product Dilution Mixing Instructions Comments Sodium hypochlorite 3% 2 gallons of bleach Not effective when area/objects 5. National Emergency Response to a Highly Contagious Animal Disease, Executive Summary. Y N Do you use strict biosecurity measures for animals, animal products, vehicles, people and equipment on your farm? Y N Do you have only one gated entrance to the animal areas on your farm to better control and monitor visitors and vehicles? Y N Have you posted signs at the farm entrance to inform visitors to stay of your farm unless absolutely necessary? Y N Have you posted a visitor biosecurity sign that clearly lists specifc measures to follow when on your farm? Animals- Livestock Y N Have you provided as much distance as possible between your animals and those of your neighbors (e. Y N Do you provide supplemental water and fence of streams or rivers to prevent your animals from drinking from them? Y N Have you educated yourself about foot-and-mouth disease and the signs of infection? Y N Do you use separate facilities, equipment, and staf to handle isolated livestock? Y N Do you prevent your vehicles or trailers from coming in contact with any other livestock that are not from your operation? Y N Do you require that any animals that have recently been acquired or have returned to the farm be quarantined for a minimum of 21 days? Y N Do prevent new additions and returning animals from sharing water, feed, facilities, or bedding with your other animals? Y N Do you always wash your hands thoroughly after any contact with sick animals to prevent disease spread to other animals? Y N Do you require your employees to wash their hands thoroughly after any contact with sick animals to prevent disease spread? ContaCt your herd veterinarian immediately if any unusual signs of illness are observed. Animals- Wildlife, Other Y N Do you prevent contact between your livestock and all cloven-hooved wildlife like deer, antelope, elk, and bufalo?

Ratios of blindness apply to countries within each subregion (Mathers and to low vision for each region were used to estimate the preva- Leonardi 2003) disulfiram 500mg low price. Regional incidence to mortality rates for Parkinson’s disease estimated by Murray and Lopez Hearing Loss 250 mg disulfiram overnight delivery. Despite the number of published studies on (1996d) were used to derive country-specific estimates for hearing loss buy cheap disulfiram 500 mg on-line, many of them use different criteria and relate incidence from the estimated country-specific mortality rates. Migraine has been ing threshold level in the better ear is 41 decibels or greater treated as a chronic disease lasting from 15 years to around averaged over 0. The case definition was or greater hearing loss (hearing threshold level in the better taken from the International Headache Society’s definition ear is 61 decibels or greater averaged over 0. Regional tion provided prevalence estimates that were quite similar estimates of the prevalence of hearing aid use were used in across most regions. For details of methods and data sources see Fewtrell and others (2004) and Pruss- Angina Pectoris. Both regional and subregional the prevalence and case fatality rates for angina pectoris prevalences for blindness and low vision were updated using (Mathers, Truelson, and others 2004). Observed correlations all available data gathered since 1980 (Resnikoff and others between the prevalence of acute myocardial infarction sur- 2004; Thylefors and others 1995). Subregional prevalences vivors and the prevalence of angina pectoris (whether inci- were estimated from more than 50 cross-sectional, dent before or after acute myocardial infarction) were used The Burden of Disease and Mortality by Condition: Data, Methods, and Results for 2001 | 83 to estimate the prevalence of angina pectoris from the mod- populations based on spirometry were available, both direct eled prevalences of acute myocardial infarction survivors. Asthma prevalence estimates were based on a case rates for acute myocardial infarction. Because accurate prevalence A total of 149 population-based studies were used to data based on spirometry are not available in many regions, derive estimates of asthma prevalence for a wide range of an alternative approach was used to infer disease occurrence countries for children, teenagers, and adults. The relative risk of mortality due to chron- European Community Respiratory Health Survey of adults ic obstructive pulmonary disease across subregions was esti- ages 20 to 44 using self-reported symptoms and bronchial mated as a function of its two leading risk factors—tobacco hyper-responsiveness (Chinn and others 1997; Pearce and smoking and indoor air pollution from solid fuel used for others 2000). Estimates from the population-based studies cooking—along with regional fixed effects (Lopez and oth- were then used to derive subregional average prevalence ers forthcoming). Data on risk factors were derived from the rates, which were assumed to apply in countries without comparative risk assessment carried out for the World specific population studies. Subregional prevalence rates for estimated regional prevalence with data from available pop- rheumatoid arthritis were derived from available published ulation studies. For regions where surveys of representative population studies using case definitions for definite or 84 | Global Burden of Disease and Risk Factors | Colin D. Subregional prevalence rates for in determining the overall health status of populations in all osteoarthritis were derived from available published popu- regions of the world. Prevalence numbers were based on regional causes dominates the overall burden of nonfatal disabling prevalence rates for edentulism estimated by Murray and conditions. The disabling burden of neuropsychiatric condi- tions is almost the same for males and females, but the major contributing causes are different. While depression is Injuries the leading cause for both males and females, the burden of An incident episode of a nonfatal injury is defined as an depression is 50 percent higher for females than for males, episode that is severe enough for the person to be hospital- and females also have a higher burden from anxiety disor- ized or that requires emergency room care (if such care is ders, migraine, and senile dementias. In higher than that for females and accounts for one-quarter of brief, the incidence of nonfatal injuries by external cause the male neuropsychiatric burden. Adult-onset hearing loss is extremely prevalent, with of health facility data provided by 18 countries in five World more than 27 percent of men and 24 percent of women aged Bank regions. For most cause categories, extrapolations 45 and over experiencing mild hearing loss or greater. The total attributable burden of disability due to alcohol use is much larger (see chapter 4). Although healthy life lost through time spent in states of less than full the prevalences of disabling conditions such as dementia health. From 1991 to 1994, average, poor health resulted in a loss of nearly eight years of the risk of premature death increased by 50 percent for healthy life globally. This once again illustrates the importance of Latin America and the Caribbean taking nonfatal conditions into account, as well as deaths, Middle East and North Africa when assessing the causes of loss of health in populations. East Asia and Pacific In 2001, the leading causes of the burden of disease in low- and middle-income countries were broadly similar to South Asia those for the world as a whole (table 3. Between ed for 36 percent of the world’s total burden of disease and 1994 and 1998, life expectancy for males improved, but injury in 2001 and adults ages 15 to 59 accounted for almost declined again significantly between 1998 and 2001 (Men 50 percent. While the proportion of the total burden of disease stantially higher burden of noncommunicable disease than borne by adults ages 15 to 59 was the same in both groups of high-income countries (figure 3. Other uninten- top four causes of the burden of disease, four nonfatal condi- tional injuries and violence were the third and fourth Table 3. Low- and middle-income countries High-income countries around 85 percent in adults ages 15 and older,the proportion 0–4 in middle-income countries has already exceeded 70 percent. Population aging and changes in the distribution of risk factors have accelerated the epidemic of noncommunicable disease in many developing countries. Injuries were also important older attributable to cancer was 6 percent in low- and mid- for women ages 15 to 44, although road traffic accidents dle income countries and 14 percent in high-income coun- were the 10th leading cause, preceded by other unintentional tries in 2001. The number of cases of lung cancer increased nearly 30 percent since 1990, largely reflecting the emergence of the tobacco epidemic in low- and middle- The Growing Burden of Noncommunicable Diseases income countries. The burden of noncommunicable diseases is increasing, Stomach cancer, which until recently was the leading site accounting for nearly half the global burden of disease for all of cancer mortality worldwide, has been declining in all parts ages, a 10 percent increase from estimated levels in 1990. Liver cancer was the third leading site, with The Burden of Disease and Mortality by Condition: Data, Methods, and Results for 2001 | 89 607,000 deaths in 2001, more than 60 percent of them in the compared with other regions. Among women, the leading cause of burden in Latin America and Caribbean countries, cause of cancer deaths was breast cancer. Globally, neuropsychiatric Group I causes also appear in the top 10 causes for this conditions accounted for 19 percent of the disease burden region, with road traffic accidents being the only non- among adults, primarily from nonfatal health outcomes. Of particular note, road traffic accidents were Injuries, both unintentional and intentional, primarily the third leading cause and congenital anomalies were the affect young adults, and often result in severe, disabling seventh leading cause. In 2001, injuries accounted for 16 percent of the Group I causes of the disease burden remained dominant adult burden of ill-health and premature death worldwide. In developed countries, suicides accounted hensive assessment of global population health, and has also for the largest share of the intentional injury burden, where- confirmed the growing importance of noncommunicable as in developing regions, violence and war were the major diseases in low- and middle-income countries. The former Soviet Union and other high-mortality has also documented dramatic changes in population health countries of Eastern Europe have rates of death and disabil- in some regions since 1990. The key findings include the ity resulting from injury among males that are similar to following: those in Sub-Saharan Africa. In addition, injury deaths are noticeably changed our perceptions of the time frames within which higher for women in some parts of Asia and the Middle substantial changes in the burden of chronic disease can East and North Africa than in other regions, partly occur and of the potential for such adverse health trends because of high levels of suicide and violence. Otherwise, limitations • Sense organ disorders, principally hearing and sight loss, in the evidence base for certain causes or regions might lead contribute significantly to disability in all regions of the to their omission, and hence to the conclusion that they world. The gap between serious lack of information on levels of adult mortality and healthy life expectancy and total life expectancy is pro- causes of death in some regions, particularly Sub-Saharan portionately highest for the low-income countries. The key need for countries is to establish a system that registers the most common causes of death for the The analysis presented in this chapter has aimed to pro- entire population without serious biases (such as an empha- duce a comprehensive and detailed assessment of the global sis on urban mortality), in which there is reasonable confi- burden of disease, based on all available relevant data. Recent experience in sparse has used the available evidence and the best available countries such as China, India, and Tanzania suggests that methods to make inferences and to assess the uncertainty sample registration based on a representative set of surveil- in resulting estimates (see chapter 5). The need for internal lance sites, and with appropriate controls and reporting pro- consistency between estimates of incidence, prevalence, cedures, can yield extremely useful information about levels, case fatality rates, and mortality rates for a given disease patterns, and causes of mortality for large populations (Setel and for consistency across diseases and injuries with and others 2005; Yang and others 2005). Low- and middle- known total levels of mortality are crucial strategies for income countries can benefit from the advantages of death making the best use of multiple sources of uncertain and registration without implementing a system of complete potentially biased data. To support such systems, pri- global and regional causes of death have been summarized ority needs to be given to developing a standardized report- in tables 3. In excess of 770 country-years of ing form for verbal autopsies and to implementing valida- death registration data and more than 3,000 additional tion studies to assess the reliability and accuracy of verbal sources of information on levels of child and adult mortali- autopsy methods. As discussed in more than 10,000 data sets relating to population health and chapters 5 and 6, new data and syntheses for major causes mortality. This represents the largest synthesis of global of child death may result in future revisions to the estimates information on population health carried out to date. Similarly, even in high-income countries, few den, even in the face of limited or missing data, to ensure population-based studies of the prevalence of chronic lung that a comprehensive overview is provided to gain a better disease or musculoskeletal conditions have been carried out. Nevertheless, substantial uncertainty ease models used to estimate the burden of disease for some remains about the comparative burden of diseases and causes. This is to become more widespread unless control programs partly an issue of valuation of health states for the construc- are more widely implemented. However, we remain sub- tion of disability weights, and partly an issue of lack of stantially uncertain about the true levels of the disease bur- information on the population-level distribution of out- den from chronic lung disease, heart disease, stroke, mental comes and the severity of health states.

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I had planned to collect personal electronic journals or diaries in addition to the data gathered from the interview guide cheap 500 mg disulfiram otc. Nevertheless buy discount disulfiram 250 mg line, triangulation was achieved by interpreting the data from two theoretical positions (feminism and social constructionism) discount 250 mg disulfiram with amex. I also used the services (on a voluntary basis) of a colleague for data interpretation. I discuss my colleague’s feedback and its impact on data interpretation in Chapter 5. Results In this study, I explored female thyroid patients’ experiences of treatment and the doctor-patient relationship. The interview questions created for the study reflected upon the following research questions: “What are the treatment experiences of women with thyroid disease? While the majority of participants expressed some type of dissatisfaction with their treatment experiences, some participants conveyed only positive comments about their experiences. Many of the participants who were dissatisfied with their treatment 116 experiences switched doctors and were ultimately satisfied with their treatment. The participants’ stories provide a comprehensive review of treatment experiences surrounding the doctor-patient relationship, doctor-patient communication, and the culture of the medical profession. In order to provide a thorough examination of the participants’ experiences, the following review of themes and subthemes includes quotes from each participant, as applicable. Theme 1: Doctor-Patient Relationship Each interview began with asking participants to describe their experience with seeking treatment for thyroid disease. The participants’ responses revealed two types of doctor-patient relationships: traditional and collaborative. Eleven of the 16 total participants (Anne, April, Carla, Diane, Jenna, Jessica, Karen, Kim, Leanne, Sarah, and Shawna) experienced traditional doctor-patient relationships. Among these participants, 8 felt unheard by their doctors, 10 felt invalidated by their doctors, 8 felt dismissed by their doctors, 4 experienced a lack of empathy from their doctors, and 3 felt disrespected by their doctors. Eight of the 11 participants who experienced a traditional doctor-patient relationship (April, Carla, Diane, Jenna, Jessica, Leanne, Sarah, and Shawna) indicated that they felt unheard by their doctors. Then of the 11 participants who experienced a traditional doctor-patient relationship (Anne, April, Carla, Diane, Jenna, Jessica, Kim, Leanne, Sarah, and Shawna) indicated that they felt invalidated by their doctors. Eight of the 11 participants who experienced traditional a doctor-patient relationship (Anne, April, Carla, Diane, Jenna, Leanne, Sarah, and Shawna) indicated that they felt dismissed by their doctors. I didn’t occur to me that he had fired me until I was telling someone else about this appointment. In his notes from our last appointment, he said it appeared I was treating myself. This surprised me quite a bit because he had always seemed to appreciate that I was a somewhat informed patient. I work at a hospital and lots of people think he has gotten less caring over the years. Four of the 12 participants who experienced a traditional doctor-patient relationship (Emily, Jessica, Leanne, and Shawna) indicated that they experienced a lack of empathy from their doctors. I work at a hospital and lots of people think he has gotten less caring over the years. Three of the 12 participants who experienced a traditional doctor-patient relationship (Carla, Leanne, and Shawna) indicated that they felt disrespected by their doctors. Thirteen of the 16 total participants (Alicia, April, Autumn, Carla, Diane, Emily, Jenna, Karen, Kari, Kim, Leanne, Michelle, and Shawna) experienced collaborative doctor-patient relationships. Among these 122 participants, 10 felt heard by their doctors, eight felt validated by their doctors, four felt unrushed by their doctors, and 12 participated in shared decision making with their doctors. Then of the 13 participants who experienced a collaborative doctor- patient relationship (Alicia, April, Autumn, Diane, Emily, Karen, Kari, Kim, Leanne, and Michelle) indicated that they felt heard by their doctors. Eight of the 13 participants who experienced a collaborative doctor-patient relationship (Alicia, April, Diane, Emily, Karen, Kim, Leanne, and Michelle) indicated that they felt validated by their doctors. Four of the 13 participants who experienced a collaborative doctor-patient relationship (Emily, Kari, Leanne, Shawna) indicated that they felt unrushed by their doctors. Twelve of the 13 participants who experienced a collaborative doctor-patient relationship (Alicia, April, Carla, Diane, Emily, Jenna, Karen, Kari, Kim, Leanne, Michelle, and Shawna) indicated that they participated in shared decision making with their doctors. While he tends to be satisfied if my numbers are within the normal range, he does listen when I tell him how I am feeling and that we need to continue working on treatment (adjusting medication dosages and testing) until I am thriving. I call her up and she says ‘just put Thyro Pero on that order and also whatever you want’ [so] I add Ferritin and B12 based on my internet research. Two of these participants (Karen and Kim) made statements that indicated a personal belief that “doctor knows best. Twelve of the 15 participants who participated in some form of self-advocacy (Alicia, Anne, April, Carla, Diane, Emily, Jenna, Karen, Kari, Kim, Leanne, and Shawna) conducted health information-seeking. Nine of the 15 participants who participated in some form of self-advocacy (Anne, April, Diane, Jessica, Karen, Kim, Leanne, Michelle, and Shawna) switched doctors. The last one is really trying to work with me, but the other two got frustrated and abusive with me because I was not tolerating the thyroid meds well. But after years of mistreatment I finally took the bull by the horns…I went through 5 Endos before I found one who knew what she was doing. If I feel a male doctor’s approach to thyroid care is wrong for me, I simply don’t go back to him and begin looking for another doctor. If I feel a male doctor’s approach to thyroid care is wrong for me, I simply don’t go back to him and begin looking for another doctor. Doctor-patient communication appeared to be influenced by the participant’s desire to be informed, the participant’s level of trust in her doctor, and by being female. Six of the 16 total participants (Anne, April, Emily, Kim, Leanne, and Michelle) expressed a desire for their doctors to inform them about the results of lab work and treatment options. In responding to interview questions regarding communication, nine out of the 16 total participants (Anne, April, Carla, Jenna, Kim, Leanne, Michelle, Sarah, and Shawna) indicated that their ability to communicate with their doctors was influenced by their level of trust in their doctors. Four of these nine participants explicitly expressed distrusting their doctors, six refused treatment, three engaged in secret-keeping, and six engaged in self-treatment. Four out of the nine participants (Carla, Leanne, Sarah, and Shawna) who indicated that their ability to communicate with their doctors was influenced by their level of trust in their doctors explicitly expressed distrusting their doctors. I have learned to get copies of them and not believe what the doctor’s office tells me. Six out of the nine participants (Anne, April, Jenna, Leanne, Michelle, and Sarah) who indicated that their ability to communicate with their doctors was influenced by their level of trust in their doctors explained that they had refused treatment. Three out of the nine participants (Kim, Leanne, and Sarah) who indicated that their ability to communicate with their doctors was influenced by their level of trust in their doctors explained that they had kept secrets from their doctors. I just told him I was seeing another doctor for my thyroid treatment…We sometimes have to resort to trickery! Six out of the nine participants (Carla, Jenna, Leanne, Michelle, Sarah, and Shawna) who indicated that their ability to communicate with their doctors was influenced by their level of trust in their doctors explained that they had engaged in self-treatment. Our local herbalist gave me a supplement which offered thyroid and adrenal support. I also was clicking on ads on the internet and read some doctor that insisted we are all iodine 133 deficient and promoting his pills. The majority of participants’ responses to questions regarding the potential influence of gender on treatment experiences revealed that the doctors’ gender had little influence on doctor-patient communication. However, participant responses indicated that being female influenced doctor-patient communication, particularly regarding the participants’ perceptions of being taken seriously and when the participants expressed emotion. Thirteen of the 16 total participants (Alicia, Anne, April, Autumn, Diane, Emily, Jessica, Karen, Kim, Leanne, Michelle, Sarah, and Shawna) indicated no preference for a male or female doctor. I wonder if a woman might be more understanding, but I feel that my [male] physician is very understanding. My previous thyroid doctor who died was a man, and he was an internal medicine doc whose special interest was in hormone treatment (of all kinds, not just thyroid). Nine out of the 16 total participants (Alicia, Anne, April, Carla, Diane, Emily, Jenna, Leanne, and Sarah) indicated that being taken seriously influenced their ability to communicate with their doctors. I do tend to get emotional which I think makes doctors give less credence to my depiction of my symptoms. Three out of the 16 total participants (Alicia, Anne, and Leanne) indicated that showing emotion influenced communication with their doctors.

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In Thirdly purchase disulfiram 250 mg on line, during in vitro testing generic 500 mg disulfiram, phage– any case disulfiram 250 mg for sale, it is not so much that robust and bacterial community interactions should be effective in vitro phage characterization is followed over relatively short time intervals crucial to successful phage therapy develop- so that bacterial growth, giving rise to ment but instead that such efforts are cheaper, substantial increases in bacterial densities, less time-consuming and frankly more does not occur over the course of experi- humane than relying entirely on animal mentation. This means, in particular, that testing to characterize phage isolates for overnight incubations of phages with bacteria bacterial killing ability. Has bacterial colonization been typically preferable to end point determin- established prior to phage application? In particular, animal or other models that reasonably unless protocols have been designed represent the actual circumstances under specifically to test for the prevention of which phage therapy is envisaged. What initiation of bacterial infections (prophylaxis), constitutes a good model for in vivo or in situ then at a minimum multiple hours should phage therapy efficacy? At a minimum, effort separate bacterial challenge and subsequent should be made to make sure that bacterial phage addition (and if testing of prophylaxis colonization along with tissue invasiveness is envisioned, then phage addition should and other infection details occur to an extent precede bacterial challenge by a substantial that is similar to that seen with typical length of time rather than being simultaneous infection presentation (see, for example, Loc- or near simultaneous to bacterial application). For An alternative approach involves applying instance, if biofilms are normally present, and phages and bacteria to different body com- have developed for days, weeks or months partments, although determining whether prior to the onset of antibacterial treatment, such approaches are truly good models for then such biofilms should also be present in determining phage-therapy efficacy should the disease model employed to explore the be the subject of rigorous pharmacokinetic potential for phage-therapy efficacy (Ramage testing rather than simply assumed. The ultimate indication of poor technique in terms of failing to allow establishment of Discussion bacterial colonization prior to phage application is the mixing of phages with Given the above considerations, I envisage a bacteria prior to bacterial challenge, although logical four-step process of initial phage- simultaneous or even just short delays therapy development: (i) rational phage between bacteria and phage addition should isolation including in terms of avoidance of also be viewed as suspect. Indeed, ofen the temperate phages as well as the carriage of result of such practices is what appear to be virulence-factor genes; (ii) in vitro phage bacterial reductions only to below minimal characterization for anti-bacterial virulence; lethal densities rather than a ‘curing’ of (iii) in vivo or in situ proof-of-principle efforts existing disease. At a minimum, therefore, using models in which efficacy is highly effort should be made during phage-therapy expected while at the same time limitations experimentation to avoid mixing bacterial of technique may be identified (particularly challenges with phages in a manner that in terms of delays between bacterial challenge mimics phage–bacterial interactions as they and phage application); and then (iv) use of can occur in broth cultures. Usually such more realistic disease models to develop avoidance will be the case given substantial clinically useful therapeutic techniques, that delays between bacterial challenge and phage is, that improve on efficacy at or beyond the addition. In short, the field of further development of phage-therapy phage therapy, even in Western literature, protocols and/or a need for identification of has moved beyond the point of proof of more effective phages. Thus, would contrast with observation of reductions if animal experimentation is indicated, then in efficacy – given substantial delays between that experimentation really ought to be bacterial challenge and phage application – properly done. This means, perhaps more serving instead as study end points, as too than anything else, that effort should be ofen is the case in the phage-therapy made to improve the accuracy of disease literature. Abedon Ultimately phage-therapy protocols practice numbers 5–8, all of which involve need to be tested against naturally occurring questions of how to properly control as well infections, although in my opinion this as reduce biases during phage-therapy represents a later step in development. Step (vi) might then incorporate controls; that is, can a phage-therapy protocol, treatment of a small number of naturally under some approximation of the best of all occurring infections, representing essentially possible circumstances, achieve phage- a limited trial. Step (vii) would then entail a therapy efficacy even if it fails to do so under fairly substantial trial, perhaps under more other, perhaps more clinically realistic, real-world conditions. This Animal testing of the treatment of human would particularly be the use of an diseases, however, may not always be approximation of passive treatment, meaning extendable beyond step (v). A Pseudomonas ear infections (see Burrowes and good rule-of-thumb definition of ‘enough’, Harper, Chapter 14, this volume, for ref- whether provided by active or passive means, erences). Here, the first publication addressed may be the achievement of a density of at phage treatment of a naturally acquired least 109 phages ml–1 to the actual physical infection in a single dog, the ‘second’ publi- location of target bacteria, or at least 108 given cation considered the treatment of naturally somewhat ideal conditions (Abedon and acquired infections in ten additional dogs, the Thomas-Abedon, 2010; Abedon, 2011a,b, ‘third’ publication was a safety and limited 2012; Curtright and Abedon, 2011). The subject of controls during phage-therapy It should be strongly stressed that experimentation is complicated by the issue positive controls are most relevant, and of double blinding of well-designed clinical arguably perhaps only relevant, if phage- trials. Thus, in addition to researcher therapy protocols fail to otherwise achieve blinding, it is important not to overlook the reasonable levels of efficacy (i. In other words, negative controls, positive controls and controlled experimental results generally are more variables. In this section, I consider best meaningful to the extent that positive Phage-therapy Best Practices 263 experimental results – phage-mediated result in poor outcomes under circumstances bacterial clearing positive controls – are in which antibiotics nevertheless are effective, demonstrably possible, such as might be except that more effort may need to be put achieved by adding more phages, employing into phage-therapy protocol development. Has a reasonable negative-treatment improve on experimental phage therapy control been used? None the ticularly should results otherwise prove less, the use of a reasonable negative control is disappointing. Thus, unquestionably important but only if those the negative control is an approximation of negative results are assuredly not simply a the normal phage-therapy protocol but one consequence of poor or otherwise insufficient that allows a normal infection outcome, as experimental technique. Clearly, the negative results, there thus should always be easiest means of ataining this outcome is to concern that sufficient effort has been made avoid applying phage formulations altogether. Above all, one This approach, however, is complicated by should always be worried that the phages the need to differentiate phage-associated employed were in some manner inadequate, therapy efficacy from efficacy that is associated that the doses used were in some manner instead with phage carriage material or other insufficient or that the rates or duration of aspects of treatment protocols that might not dosing were to some degree in need of further be employed in the absence of phage increase. Particularly, non-phage compon- whether supplying more phages will result in ents of phage formulations can contain greater overall levels of bacterial killing. Therefore, as phage-therapy is not the only kind of positive control that is negative controls, it is beter practice to use possible in phage experiments. For example, some kind of mock treatment that is a good if one is comparing phage performance with approximation of the phage formulation, only a normal standard of care, then an antibiotic- lacking in active phages. The use of Phages can be removed from formu- such a control, however, does not substitute lations via filtration or destroyed via heating. Formulations otherwise can be created in a This is because the question that is being phage-free manner that approximates the addressed with phage-killing positive phage-generated material. Alternatively, controls is not that of phage therapy efficacy phages can be sufficiently purified prior to in comparison with other treatment options use such that a simple buffer, as equivalent to but instead whether, in the absence of desired that in which the phages have been sus- levels of bacterial-treatment success, in- pended, may be employed as the negative sufficiencies in dosing might be to blame. Unfortunately, not much effort has other words, there is litle information that been put into determining whether these may be obtained should phage application various substitutions provide similar or even 264 S. Abedon reasonable performance as true phage- preparation, and lysis has the potential to negative controls. None the less, it is crucial release a number of bacterial toxins, in to employ negative controls during phage- particular endotoxin from Gram-negative therapy testing that allow a definitive bacteria (Gill and Hyman, 2010). To guard distinction between phage-mediated efficacy against the introduction of these toxins into and efficacy that is due instead to non-phage patients, phage preparations can be purified. Even given such purification, in the course of experimentation an important control is to show that phage application in and of itself will not lead to toxicity. These such controls is not just to show that methods are important for the sake of formulations as well as the phages themselves removing biases from what can be subjective that are employed in a given study are non- observations, such as how sick the subject is. Should remove biases in the treatments themselves, formulation toxicity in fact turn out to be the particularly if the treatments are relatively case, then production or delivery approaches complicated or, instead, if there is any potential may be modified. For example, greater lysate that subjects may be chosen or taken care of purification or less invasive application – the differently depending on the treatment type. Note should be expected to display double that in vitro testing of phage formulations, blinding, then at a minimum some effort especially for endotoxin presence, is also should be made to remove biases from in vivo routinely available (Boratynski et al. In reduction such as blinding has been this section, I consider issues of dosing employed. Has multiple or continuous dosing An ongoing concern with regard to phage been attempted? This occurs because literature is the notion that phages, as bacterial lysis is involved in phage stock potentially self-amplifying antibacterials, Phage-therapy Best Practices 265 ought to be efficacious even if applied only sufficient phage numbers is an obvious once. By contrast, it is atypical among pharma- dosing criterion given consideration of phage ceuticals to demand efficacy following only a therapy from a pharmacological perspective. For that that phages will achieve sufficient densities to reason, phage-therapy protocols, particularly eradicate bacteria (Abedon and Thomas- where human treatment is the goal, should Abedon, 2010; Abedon, 2010a, 2011a,b, 2012). In failed to provide sufficiently efficacious addition, one should question whether a results, strategies ought to be explored that sufficient frequency or number of doses was are aimed at improving outcomes. Such applied, as well as whether the phages strategies might include providing phages themselves have sufficient antibacterial multiple times over the course of treatment, activity. Thus, for example, if one observes a providing phages with increasing frequency single log killing with an application of 107 (e. It is dangerous, however, to Further considerations include the assume that single dosing represents a default following: (i) when employing phages that means by which phage therapy is imple- have been engineered to not reproduce, such mented. In particular, where phage therapy is as to avoid in situ bacterial lysis, which will actually practised clinically, such as in release endotoxin (Bull and Regoes, 2006; Georgia and Poland, single dosing does not Goodridge, 2010; Abedon and Thomas- represent the standard of care (Kuter et al. Has there been inappropriate reliance not a function of either bacterial densities or on active treatment? Lastly, (iv) if bacterial densities it can take hours, days, contamination of formulations with bacterial weeks or even longer for a reasonable fraction lysis products such as endotoxin is a problem, of bacteria to become phage adsorbed then using more phages per treatment will (Goodridge, 2008; Hagens and Loessner, result in patient exposure to more of these 2010; Abedon, 2011a,d, 2012). Thus, while using more phages per To reiterate these first two points, if dose can be an important consideration in insufficient phage densities are present optimizing phage-therapy protocols, there within the environment, then insufficient are potential tradeoffs associated with this bacterial killing will occur and such strategy, although these are all tradeoffs that insufficiencies in bacterial killing are possible may be readily explored experimentally. Has the concept of ‘multiplicity of the likelihood or rate at which a given infection’ been used correctly? Furthermore, this statement only a small fraction of susceptible bacteria is different from the question of the overall remain uninfected.

Y. Ramon. Truman State University. 2019.

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