Combivir

Suks Minhas MD, FRCS(Urol)

• Consultant Urologist
• University College Hospital
• London, UK

In an observational study involving patients in a hospital in Wisconsin between 2000 and 2005 medications and grapefruit juice cheap 300 mg combivir overnight delivery, it was shown that C medicine quiz combivir 300mg lowest price. One hypothesis presented was antibiotic use disrupting the beneficial gut bacteria symptoms 2 weeks pregnant buy combivir no prescription, but it is conceivable that increased exposure to glyphosate is contributing to this increase medications nursing cheap combivir online american express. A higher level of p-cresol in the urine has been associated with lower residual sulfonation [67] and with autism [68] medicine for sore throat cheap 300mg combivir. In a case-control study treatment spinal stenosis order 300 mg combivir with visa, children with autism were found to be significantly more likely to have been formula-fed rather than breast-fed [71]. The study did not distinguish between organic and non-organic formula, but one can surmise that non-organic soy formula might be contaminated with glyphosate, and this could be a contributing factor to both the autism and the C. Urinary bacterial metabolites of phenylalanine, such as benzoic and phenylacetic acids, and of tyrosine (p-hydroxybenzoic acid and p-hydroxyphenylacetic acid) have been found to be elevated in association with several different diseases reflecting impaired intestinal resorption, including coeliac disease, cystic fibrosis, and unclassified diarrhoea [72]. High concentrations of an abnormal phenylalanine metabolite have been found in the urine of people with autism and schizophrenia, up to 300x normal adult values, which is likely due to multiple species of anaerobic bacteria in the Clostridium genus [73]. Others have detected abnormally high concentrations of hippurate in the urine in association with autism [74]. Thus a variety of different compounds representing a deflection of aromatic amino acid synthesis towards oxidized benzene derivatives have been found in association with various digestive disorders and neurological disorders. Studies have convincingly shown an inflammatory mucosal immunopathology in children with regressive autism characterized by infiltration of intestinal epithelial lymphocytes [76]. As will be seen in the next section, we propose that this dysbiosis is caused principally by impaired sulfate supply to the mucosa, and that the toxic phenolic compounds both assist in correcting this deficiency and induce inflammatory responses due to their oxidizing effects. Sulfate Transport Impairment and Phenol Synthesis Autism is a disorder involving impaired social skills and neurodevelopmental delay that has reached epidemic proportions in recent years, with one in 50 children born in the United States today now classified on the autism spectrum, according to the U. Impaired sulfur oxidation and low levels of serum sulfate have been established in association with autism since 1990, as evidenced by the following quote from [77]: “These results indicate that there may be a fault either in manufacture of sulphate or that sulphate is being used up dramatically on an unknown toxic substance these children may be producing” (p. In this section, we develop a novel hypothesis for the effect of glyphosate on aromatic amino acids in plants and microbes. Our arguments depend upon the observation that glyphosate, a short carbon-nitrogen chain with a carbonyl group and a phosphate group, is a strong anionic kosmotrope, since both carbonate and phosphate have this property. Kosmotropes and chaotropes represent opposite extremes on the Hofmeister series [78,79], where kosmotropes tend to structure the water surrounding them and to desolubilize proteins, whereas chaotropes destructure the water and solubilize proteins. Phenolic compounds like p-cresol can be readily sulfated in the gut, and this provides an opportunity to transport sulfate through the hepatic portal vein in the presence of glyphosate. The ring supports a charge distribution that diffuses the negative charge and suppresses the water-structuring properties of sulfate, thus preventing the vascular disturbances. A single phenol can perform this feat multiple times, as the sulfate can be attached to the phenol in the colon via a phenol sulfotransferase, and the liver utilizes sulfatases and sulfotransferases to transfer the sulfate moiety from the phenol to an available substrate, typically a xenobiotic or a sterol [82]. Thus, phenols could be responsible for supplying the sulfate critically needed to detoxify xenobiotics and bile acids and to produce various sterol sulfates, as well as supplying sulfate to the pancreas to be incorporated into mucopolysaccharides being released into the gut along with proteases by acinar cells [83]. In this scenario, the glyphosate itself, due to its kosmotropic properties, is disrupting the transport of free sulfate, and therefore the aromatic amino acids are oxidized into various phenolic compounds in order to compensate for this problem. Although flavonoids are generally considered to be beneficial to health, the biological mechanisms behind their benefit are not yet established. These authors propose that monophenolic derivatives are likely produced through ring fission of flavonoids by the gut microflora in the colon. In fact, we hypothesize that their role in sulfate transport is the reason for their abundant synthesis in plants in the presence of glyphosate at the expense of tryptophan [29]. Since they are less toxic than monophenols, they become attractive for sulfate transport in the presence of glyphosate. Schematic of cyclical process that could be utilized to transport sulfate from the gut to the liver in the face of glyphosate contamination in the hepatic portal vein. Phenolic compounds derived from aromatic amino acids would be cycled back and forth between the gut and the liver, sulfated during transport from the gut to the liver and glucuronylated during transport back from the liver to the gut. Ultimately, a sulfate reducing bacterium could metabolize the phenol, consuming sulfate. Phenol sulfatase Glyphosate Phenol sulfate Phenyl glucuronide Hepa c portal vein SulfateͲ Phenol sulfotransferase reducing Bacteria the fact that glyphosate suppresses both alkaline and acid phosphatase activity in in vitro assays [88] as well as extracellular alkaline phosphatase synthesis in algae [89] suggests that phosphate faces the same problem as sulfate in plants, in the presence of glyphosate, and hence enzymatic activity that produces free phosphate is suppressed. It is interesting to note that autism is associated with elevated serum levels of pyridoxal phosphate (vitamin B6) even in the absence of supplements [90]. Despite this, supplemental B6 has been shown to alleviate symptoms of autism [91,92]. We hypothesize that vitamin B6 is exploited to transport phosphate safely in the presence of glyphosate. The pyridoxal ring distributes the negative charge on the phosphate anion in the same way that phenols distribute the charge on sulfate, thus allowing phosphate to be transported in a non-kosmotropic form. Glyphosate’s kosmotropic effects can be counteracted through buffering of chaotropes in the blood, and this could be a factor in the increased levels of both ammonia [93] and various oxides of nitrogen, including nitric oxide, nitrite, and nitrate [94–96] observed in association with autism. Autism is also associated with a decreased ability to sulfate and hence detoxify acetaminophen, which aligns with insufficient sulfate bioavailability. A genetic defect in the phenol sulfotransferase gene is associated with autism [77]: this enzyme becomes more essential in the context of glyphosate contamination. All of these observations can potentially be explained by the effects of glyphosate on the gut bacteria and on the blood stream. Both colitis and Crohn’s disease are associated with sulfate depletion in the gut [102], which could be caused by the impaired sulfate transport problem induced by glyphosate exposure. An overgrowth of the sulfur-reducing bacterium, Desulfovibrio, has been found in association with autism [103]. Sulfate-reducing bacteria can utilize aliphatic and aromatic hydrocarbons as electron donors, and therefore they can play an important role in detoxifying toxic phenolic compounds [104–108]. Thus, the presence of Desulfovibrio in the gut may serve a dual purpose by metabolizing phenolic compounds while also disposing of free sulfate, which could be problematic if allowed to enter the blood stream in the presence of glyphosate. Thus, we hypothesize that, in the context of glyphosate in the vasculature, aromatic amino acids are diverted into phenolic compounds which can safely transport sulfate from the gut to the liver. The liver can then transfer the sulfate to another metabolite, such as a steroid, and then ship the phenol back to the digestive system for another round via the bile acids following glucuronidation [108]. Possibly after multiple rounds, the phenol is finally metabolized by a sulfate-reducing bacterium in the colon. In [110], it was shown that aromatase activity is disrupted in human placental cells at a concentration 100 times lower than that recommended in agricultural use. Retinoic acid plays a key role in embryonic development, where its tightly-regulated concentration levels impact developmental stages [112]. The treated embryos were highly abnormal: the frog embryos developed into tadpoles with cranial deformities, and microcephaly was observed in the chick embryos. Thus, if this enzyme is suppressed by glyphosate, it would explain the observed effect that glyphosate enhances levels of retinoic acid in embryonic development. A study conducted in 1998 demonstrated that glyphosate inhibits cytochrome P450 enzymes in plants [116]. The fusion protein was assayed for activity level in hydrolyzing a benzo(a)pyrene, in the presence of various concentrations of glyphosate. At 15 microM concentration of glyphosate, enzyme activity was reduced by a factor of four, and by 35 microM concentration enzyme activity was completely eliminated. The mechanism of inhibition involved binding of the nitrogen group in glyphosate to the haem pocket in the enzyme. A more compelling study demonstrating an effect in mammals as well as in plants involved giving rats glyphosate intragastrically for two weeks [117]. It is plausible that glyphosate could serve as a source for carcinogenic nitrosamine exposure in humans, leading to hepatic carcinoma. N-nitrosylation of glyphosate occurs in soils treated with sodium nitrite [118], and plant uptake of the nitrosylated product has been demonstrated [119]. Beginning in around 2006, an alarming die-off of honeybees became apparent in the United States, and researchers are still struggling to understand what is causing this die-off [124]. At first glance, pesticides might be more highly suspect, since bees are, after all, an insect. A study comparing bees exposed to glyphosate and/or Roundup against a control population demonstrated a significantly higher mortality rate in the glyphosate-exposed bees (p < 0. Neonicotinoids such as imidacloprid and clothianidin can kill bees, and have been implicated in colony collapse disorder [128]. However, this toxic effect is likely synergistic in combination with glyphosate, as would occur with bees ingesting herbicide-contaminated pollen. Glyphosate is an organophosphate, and a study of human self-poisoning has demonstrated that organophosphate ingestion synergistically greatly enhances the toxicity of ingested neonicotinoids [129]. The Path to Obesity Having established a plausible mechanism whereby glyphosate’s effects on gut bacteria would lead to depleted sulfate supplies in the gut with resulting inflammatory bowel disease, we now turn our attention towards the likely consequences of the resulting “leaky gut syndrome. These chemicals are better known for causing weight loss at high exposure levels, and this apparent paradox can be explained with respect to glyphosate, by invoking its known effect of depleting tryptophan in plants and microbes. In this section we will explain how glyphosate’s depletion of tryptophan bioavailability can lead to obesity, and in Section 6 we will provide evidence that extreme depletion of tryptophan in the absence of obesity can cause severe impairment of the intestinal barriers, resulting in weight loss and anorexia, due to an inability to transport critical micronutrients across the damaged gut barrier. Tryptophan is an essential amino acid, meaning that mammalian cells cannot synthesize it. Serum tryptophan depletion leads to serotonin and melatonin depletion in the brain [131]. Since serotonin (derived from tryptophan) is a potent appetite suppressant [132], it follows that serotonin deficiency would lead to overeating and obesity. As we have seen, tryptophan supplies could be depleted both in plant-based food sources and through impaired tryptophan synthesis by gut bacteria as direct effects of glyphosate. The observed 20-fold increase in the synthesis of tryptophan-derived polyphenolic flavonoids in the context of glyphosate provides strong evidence of impaired tryptophan synthesis [29]. It becomes the (sole) precursor to the synthesis of the neurotransmitter serotonin and the hormone melatonin [131]. Thus, low serum tryptophan levels translates into a tendency towards weight gain due to suppressed serotonin signaling [132]. Illustration of tryptophan pathways in the body and the adverse effect of glyphosate on tryptophan bioavailability. Therefore, it is expected that inflammation in the gut would lead directly to serum tryptophan depletion, thus further reducing the bioavailability of tryptophan to the liver. Studies have confirmed that serum tryptophan levels are low in association with obesity [142,143]. In [143], plasma tryptophan levels were monitored several times over the course of a twenty-four hour period, and it was confirmed that serum tryptophan levels were chronically depressed, and the levels of other competing large neutral amino acids were elevated, in obese subjects compared to controls. A recent experiment involving transferring a strain of endotoxin-producing bacteria from the gut of an obese human to the sterile gut of germ-free mice demonstrated the dramatic obesogenic effect that over-production of endotoxin by gut bacteria can have [144]. These mice became obese over a 16-week trial period, when concurrently placed on a high-fat diet, and the obesity was associated with a low-grade chronic inflammatory state. Control germ-free mice on the same diet but without the infective agent did not become obese. It was hypothesized that chylomicrons produced for fat transport became a vehicle for endotoxin delivery to blood serum and subsequently to the liver and body fat stores, since inflammatory cytokines were found predominantly in the liver and epididymal fat pad rather than in the ilium. Since glyphosate induces a shift in gut bacteria towards endotoxin-producers, this effect can conceivably explain the association of a high-fat diet with obesity [145]. The obesity epidemic began in the United States in 1975, simultaneous with the introduction of glyphosate into the food chain, and it has steadily escalated in step with increased usage of glyphosate in agriculture (see Figure 1 in [146]). While it is common knowledge that Americans are continuing to grow more and more obese with each passing year [147,148], there may be less awareness that obesity aligns with glyphosate usage elsewhere in the world [149]. For example, South Africa arguably has the highest obesity rates in all of Africa [150], and it is also the African country that has most heavily embraced glyphosate usage since the 1970’s and has freely adopted genetically modified crops with little regulation [151,152]. Here, we argue that severe tryptophan deficiency without sufficient fat stores to harbor toxins and supply sterol sulfates can result in an inability to control microbial invasion as a consequence of impaired release of antimicrobial peptides. This can lead, paradoxically, to anorexia nervosa, resulting in a highly inflamed digestive system, pathogenic penetration through leaky intestinal epithelium, uncontrollable diarrhea, and subsequent anorexia. However, a more important factor may be the ability of adipose tissue to directly supply sulfated steroids. The sulfotransferase that sulfates serotonin, thus inactivating it, is found in many tissues, including brain, heart, liver, lung, kidney and spleen [154]. Insufficient sulfate supply would likely compromise this function, leading to poor serotonin regulation. There is an interesting connection between levels of serotonin and sterol sulfates in the blood serum. This would also reduce the demand on phenols to transport sulfate and therefore alleviate the inflammatory gut disorder, restoring homeostasis. An important study elucidating the processes leading to inflammatory bowel disorder was conducted on male Ace2 knockout mice (Ace2í/y) [13]. They responded to dextran sodium sulfate exposure with a much more severe colitis attack than their control littermates, leading to enhanced infiltration of inflammatory cells, increased intestinal bleeding, severe diarrhea, and weight loss. A series of further experiments revealed that a similar response could be provoked in the control mice by providing them with a diet that was specifically deficient in tryptophan. It is conceivable that the severe deficiency in tryptophan led to restricted protein synthesis in macrophages, preventing the synthesis of the antimicrobial peptide. Furthermore, the distribution of gut bacteria was profoundly affected by the Ace2í/y phenotype and by tryptophan deprivation. Thus, severe tryptophan deficiency, as might be induced by glyphosate’s interference with tryptophan synthesis in plants and microbes, can lead to an extreme inflammatory bowel disease that would severely impair the ability to absorb nutrients through the gut, due to inflammation, bleeding and diarrhea. This could easily explain the alarming increases that have been seen recently in inflammatory bowel diseases [16,17,160]. These enzymes participate in oxidation, peroxidation and reduction of compounds ranging from pharmaceutical drugs to environmental chemicals to endogenous bioactive molecules [123]. Bile acids act as powerful detergents to aid in the digestion of fats, and also provide a pathway for disposal of oxysterols.

When delivered orally medications covered by medicare buy discount combivir 300 mg on line, Synthetic Biotic medicines are designed to act from the gut to compensate for the dysfunctional metabolic pathway with the intended consequence of reducing the systemic levels of the toxic metabolites medications for bipolar disorder purchase combivir in united states online. In these conditions ammonia accumulates in the body and becomes toxic leading to neurocognitive crisis and risk of long-term cognitive or behavioral impairment medications and breastfeeding buy combivir 300mg fast delivery, coma or death treatment abbreviation combivir 300mg without prescription. There are no currently approved pharmaceutical therapies for these disorders treatment zinc poisoning cheap combivir 300 mg without prescription, ultimately resulting in patients relying on liver transplants when possible medicine 7767 order combivir with amex. Synthetic Biotic medicines are designed to locally deliver combinations of complementary therapeutics to treat these complex disease states. We currently operate in one reportable business segment—the discovery and development of Synthetic Biotic medicines. To date, we have dedicated substantially all of our activities to the research and development of our product candidates. We have not generated any revenue to date from product sales and have incurred significant operating losses since our inception in 2014. As of December 31, 2017 and 2016, we had an accumulated deficit of approximately $71. We expect our expenses and capital requirements will increase substantially in connection with our ongoing activities, as we: complete preclinical studies, initiate and complete clinical trials for product candidates;. contract to manufacture product candidates;. advance research and development related activities to expand our product pipeline;. seek regulatory approval for our product candidates;. maintain, expand and protect our intellectual property portfolio;. hire additional staff, including clinical, scientific, and management personnel;. expand our existing infrastructure and secure space in a facility to support continued growth in our research and development efforts; and. add operational and finance personnel to support product development efforts and to support operating as a public company. We do not expect to generate product revenue unless and until we successfully complete clinical development and obtain regulatory approvals for our product candidates, either alone or in collaboration with third parties. If we obtain regulatory approval for any of our product candidates, we expect to incur significant expenses related to developing our internal commercialization capability to support product sales, marketing and distribution. Accordingly, we anticipate that we will seek to fund our operations through public or private equity or debt financings, collaborations or licenses, capital lease transactions or other available financing transactions. However, we may be unable to raise additional funds through these or other means when needed. Because of the numerous risks and uncertainties associated with product development, we are unable to predict the timing or amount of increased expenses or when or if it will be able to achieve or maintain profitability. We expect our revenue to fluctuate for the foreseeable future as it is principally based on the achievement of research and development milestones under our collaboration agreement with AbbVie. Research and Development Expense Research and development expense consists of expenses incurred in connection with the discovery and development of our product candidates, including the conduct of preclinical and clinical studies and product development, which are expensed as they are incurred. These expenses consist primarily of: compensation, benefits and other employee related expenses;. supplies to support our internal research and development efforts;. research and development related facility and depreciation costs; and. third-party contract costs relating to research, process and formulation development, preclinical and clinical studies and regulatory operations. The lengthy process of securing regulatory approvals for new drugs requires the expenditure of substantial resources. Any delay or failure to obtain regulatory approvals would materially adversely affect our product candidate development efforts and our business overall. Given the inherent uncertainties of pharmaceutical product development, we cannot estimate with any degree of certainty the likelihood, timing or cost of obtaining regulatory approval and marketing our product candidates and thus, when, if ever, our product candidates will generate revenues and cash flows. The successful development of our product candidates is highly uncertain and subject to a number of risks. We invest carefully in our pipeline, and the commitment of funding for each subsequent stage of our development programs is dependent upon the receipt of clear, supportive data. We anticipate that we will make determinations as to which additional programs to pursue and how much funding to direct to each program on an ongoing basis in response to the scientific and clinical data of each product candidate, as well as the competitive landscape and ongoing assessments of such product candidate’s commercial potential. We expect our research and development costs will be substantial for the foreseeable future. We track direct research and development expenses, consisting principally of external costs, such as costs associated with contract research organizations and manufacturing of preclinical and clinical drug product and other outsourced research and development expenses to specific product programs. Costs related to specific product candidates are tracked upon the selection of a product candidate. We do not allocate employee and consulting related costs, costs associated with our platform and facility expenses, including depreciation or other indirect costs, to specific product candidate programs because these costs are deployed across multiple product candidate programs under research and development and, as such, are separately classified. Other costs include the legal costs of pursuing patent protection of our intellectual property, general and administrative related facility and information technology infrastructure costs and professional fees for accounting and legal services. These increases include legal fees, accounting fees, costs for director and officer liability insurance, fees for investor relations services and costs associated with implementing and complying with corporate governance, internal controls and similar requirements applicable to public companies. Other Income (Expense) Interest and investment income consists primarily of interest income earned on investments. Critical Accounting Policies and Estimates Our discussion and analysis of our financial condition and results of operations is based upon our consolidated financial statements prepared in accordance with generally accepted accounting principles in the U. The preparation of these financial statements requires us to make certain estimates and assumptions that affect the reported amounts of assets and liabilities, the reported amounts of revenues and expenses during the reported periods and related disclosures. These estimates and assumptions, including those related to revenue recognition, research and development expenses and accruals and equity-based compensation are monitored and analyzed by us for changes in facts and circumstances, and material changes in these estimates could occur in the future. These critical estimates and assumptions are based on our historical experience, our observance of trends in the industry, and various other factors that are believed to be reasonable under the circumstances and form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from our estimates under different assumptions or conditions. We believe that the application of the following accounting policies, each of which require significant judgments and estimates on the part of management, are the most critical to aid in fully understanding and evaluating our reported financial results. Our significant accounting policies are more fully described in Note 2, “Summary of Significant Accounting Policies”, to our consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K. Revenue Recognition We generate revenue through our collaboration agreement with AbbVie for the development and commercialization of product candidates. The terms of this agreement include payment to us of one or more of the following: nonrefundable, up-front license fees; milestone payments; and royalties on product sales. We recognize revenue for each unit of accounting when there is persuasive evidence that an arrangement exists, delivery has occurred or services have been rendered, the price is fixed or determinable, and collectability is reasonably assured. We record amounts we receive prior to satisfying the revenue recognition criteria as deferred revenue in our consolidated balance sheets. Amounts expected to be recognized as revenue within the 12 months following the balance sheet date are classified as current deferred revenue. When we evaluate revenue from agreements, we consider the nature and contractual terms of the arrangement and the nature of our business operations to determine the classification of the transactions. When we are an active participant in the activity and exposed to significant risks and rewards dependent on the commercial success of the collaboration, we will record transactions on a gross basis in the consolidated financial statements and describe the rights and obligations under the collaborative arrangement in the notes to the consolidated financial statements. We account for those deliverables as separate elements when: (i) the delivered item(s) has value to the customer on a stand‑alone basis and (ii) if the arrangement includes a general right of return relative to the delivered item(s), delivery or performance of the undelivered item(s) is considered probable and substantially within our control. The determination that multiple elements in an arrangement meet the criteria for separate units of accounting requires us to exercise our judgement. We consider such factors as the research, manufacturing and commercialization capabilities of the collaboration partner; our retention of any key rights; and the availability of the associated expertise in the general marketplace. In addition, we consider whether the collaboration partner can use the other deliverable(s) for their intended purpose without the receipt of the remaining element(s), whether the value of the deliverable is dependent on the undelivered item(s) and whether there are other vendors that can provide the undelivered element(s). In situations where we have identified multiple units of accounting, the arrangement consideration that is fixed or determinable is allocated among the separate units of accounting using the relative selling price method. We recognize as revenue, upon delivery, arrangement consideration attributed to deliverables that have stand‑alone value from the other deliverables to be provided in an arrangement. For deliverables that do not have stand‑alone value from the other deliverables to be provided in an arrangement, we recognize revenue over the estimated performance period, as the arrangement would be accounted for as a single unit of accounting. If there is no discernible pattern of performance and/or objectively measurable performance measures do not exist, then we recognize revenue under the arrangement for the single unit of accounting on a straight‑line basis over the period it expects to complete its performance obligations. Alternatively, if the pattern of performance in which the service is provided to the customer can be determined and objectively measurable performance measures exist, then we recognize revenue under the arrangement using the proportional performance method. At the inception of an arrangement that includes milestone payments, we evaluate whether each milestone is substantive and at risk to both parties on the basis of the contingent nature of the milestone. This evaluation includes an assessment of whether: (i) the consideration is commensurate with either our performance to achieve the milestone or the enhancement of the value of the delivered item(s) as a result of a specific outcome resulting from our performance to achieve the milestone, (ii) the consideration relates solely to past performance and (iii) the consideration is reasonable relative to all of the deliverables and payment terms within the arrangement. We use considerable judgement and evaluates factors such as the scientific, clinical, regulatory, commercial and other risks that must be overcome to achieve the respective milestone and the level of effort and investment required to achieve the respective milestone in making the assessment whether a milestone is substantive. Assuming all other revenue recognition criteria are met, we recognize revenue associated with substantive milestones upon successful accomplishment of each milestone and we recognize revenue for milestones that are not considered substantive over the remaining period of performance. To date, we have recognized one substantive milestone under our AbbVie collaboration agreement. Payments received or reasonably assured after performance obligations are fully met are recognized as earned. Because the recognition of a substantive milestone under a collaboration agreement typically requires the completion of a number of activities conducted over a significant period of time, the expenses related to achieving the milestone often are incurred prior to the period in which the milestone payment is recognized. When we achieve milestones that we consider substantive under our collaboration, we may experience significant fluctuations in our revenue from quarter to quarter and year to year depending on the timing of achieving such substantive milestones. The period of performance over which the revenues are recognized is typically the period over which the research and/or development is expected to occur. As a result, we often are required to make estimates regarding drug development and commercialization timelines for compounds being developed pursuant to a collaboration or license agreement. Because the drug development process is lengthy and our collaboration and license agreements typically cover activities over several years, this approach has resulted in the deferral of revenue into future periods. In addition, because of the many risks and uncertainty associated with the development of drug candidates, our estimates regarding the period of performance may change in the future. Any change in our estimates could result in substantial changes to the period over which the revenues from an up-front license fee are recognized. To date, we have had no material changes to our estimated period of continuing involvement under our AbbVie collaboration agreement. Research and Development Expense All research and development expenses are expensed as incurred. Research and development expenses comprise costs incurred in performing research and development activities, including compensation, benefits and other employee costs; equity‑based compensation expense; laboratory and clinical supplies and other direct expenses; facilities expenses; overhead expenses; fees for contractual services, including preclinical studies, clinical trials, clinical manufacturing and raw materials; and other external expenses. Nonrefundable advance payments for research and development activities are capitalized and expensed over the related service period or as goods are received. When third-party service providers’ billing terms do not coincide with our period-end, we are required to make estimates of our obligations to those third parties, including clinical trial costs, contractual service costs and costs for supply of our drug candidates, incurred in a given accounting period and record accruals at the end of the period. We base our estimates on our knowledge of the research and development programs, services performed for the period and the expected duration of the third-party service contract, where applicable. Please read Note 2, “Summary of Significant Accounting Policies” to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for a further discussion of research and development expenses. We measure equity-based compensation to employees and directors based on the grant date fair value of the awards, net of estimated forfeitures, and recognize the associated expense in the consolidated financial statements over the requisite service period of the award, which is generally the vesting period. Equity‑based compensation costs for nonemployee awards are recognized as services are provided, which is generally the vesting period, on a straight‑line basis. We believe that the fair value of the equity is more reliably measurable than the fair value of the services rendered. The fair value of the award granted to a nonemployee is remeasured at each reporting date until performance is completed with any increase or decrease in fair value recorded as equity‑based compensation expense. We record the expense for equity grants subject to performance-based milestone vesting over the remaining service period when we determine that achievement of the milestone is probable. Management evaluates when the achievement of a performance-based milestone is probable based on the relative satisfaction of the performance conditions as of the reporting date. The Black-Scholes option-pricing model, and the Black Scholes with barrier option pricing model used for valuing incentive units, requires the use of highly subjective assumptions to estimate the fair value of equity-based awards. If we had made different assumptions, equity-based compensation expense, net loss and net loss per common share/unit could have been significantly different. These assumptions include: Fair market value of our common stock: Prior to our Merger, our common stock and common units were not publicly traded so our Board of Directors was required to estimate its fair market value as described below. Subsequent to the Merger, it is determined as the closing trading price of our common stock. Industry peers consist of several public companies in the biopharmaceutical industry that are similar in size, stage of life cycle and financial leverage. We intend to continue to consistently apply this process using the same or similar public companies until a sufficient amount of historical information regarding the volatility of our own common stock price becomes available, or unless circumstances change such that the identified companies are no longer similar to us, in which case, more suitable companies whose share prices are publicly available would be utilized in the calculation. Therefore, we have opted to use the “simplified method” for estimating the expected term of our stock options. Since our incentive units did not have an expiration date, we use a probability-weighted estimated term to a liquidity event. Treasury securities with maturities similar to the expected term at the time of grant. Prior to the Merger, the Board of Directors determined the estimated per share fair market value of our common stock and common units at various dates considering contemporaneous valuations performed in accordance with the guidance outlined in the American Institute of Certified Public Accountants Practice Aid, Valuation of Privately-Held Company Equity Securities Issued as Compensation, or the Practice Aid. The fair market value of the common stock and common units was determined by the Board of Directors at each award grant date based on assumptions, each of which are subjective and generally require judgement and estimation by management, including results obtained from independent third party valuations, our financial position and historical financial performance, the status of technological developments within our product candidates, the composition and ability of the research and management team, an evaluation or benchmark of our competition, the business climate in the marketplace, the illiquid nature of the common stock and common units, arm’s length sales of our capital stock (including convertible preferred stock), the effect of the rights and preferences of the preferred stock, and the prospects of a liquidity event. The Board of Directors determined the threshold price for an incentive unit, which was the price at which an incentive unit would have had a liquidation value of zero, considering the fair value of our assets and performed an analysis to determine the per unit amount that a holder would have received upon a distribution event. In determining the fair value of our assets, we relied on independent third-party valuations, which take into account a variety of factors, including our financial position and historical financial performance, the status of technological developments within our products, the composition and ability of the research and management team, an evaluation or benchmark of its competition, the business climate in the marketplace, the illiquid nature of the common units and incentive units, arm’s-length sales of our equity, the effect of the rights and preferences of the preferred unit holders, and the prospects of a liquidity event, among others. Results of Operations the following discussion summarizes the key factors our management believes are necessary for an understanding of our consolidated financial results. Year ended December 31, 2017 2016 (in thousands) Revenue $ 2,444 $ 444 Operating expenses: Research and development 30,341 15,010 General and administrative 12,927 6,398 Total operating expenses 43,268 21,408 Loss from operations (40,824) (20,964) Other income (expense): Interest and investment income 504 17 Interest expense (57) (7) Other income (expense), net 447 10 Net loss $ (40,377) $ (20,954) 64 Year Ended December 31, 2017 Compared to Year Ended December 31, 2016 Revenue Years Ended December 31, Change 2017 2016 $ % (dollars in thousands) Revenue $ 2,444 $ 444 $ 2,000 450% Revenue was $2. Operating Expenses Years Ended December 31, Change 2017 2016 $ % (dollars in thousands) Operating expenses: Research and development $ 30,341 $ 15,010 $ 15,331 102% General and administrative 12,927 6,398 6,529 102% Total operating expenses $ 43,268 $ 21,408 $ 21,860 102% Research and Development Expense Research and development expense was $30. These fees related to costs of preparing for and being a public company, such as audit fees, investor relations, consulting, filing fees and insurance for our directors and officers. Other professional fee increases were related to corporate legal fees for our May 2017 reorganization and for patent-related legal fees to support our patent portfolio. These increases in interest and investment income were partially offset by an increase in interest expense associated with the new capital leases. Liquidity and Capital Resources We have incurred losses since our inception on March 14, 2014 and, as of December 31, 2017, we had an accumulated deficit of approximately $71. We have financed our operations to date primarily through the sale of preferred stock, common stock, preferred units, payments received under our AbbVie collaboration agreement, interest earned on investments, and the merger with Mirna. In January 2018, we sold 5,130,000 shares of our common stock through a firm commitment, underwritten public offering at a price to the public of $9. The underwriters elected to exercise their option to purchase 769,500 additional shares of our common stock at the public offering price, less underwriting discounts and commissions.

The intervention aims to normalize psychomotor development facilitating movement sequences and patterns in a more organized symptoms 28 weeks pregnant purchase combivir with amex, automatic medicine dictionary combivir 300 mg with visa, economical way with a better voluntary control treatment yeast infection men discount combivir 300mg amex. In this range of age medications and grapefruit juice buy 300mg combivir otc, gross and fine motor demands become more complex and therefore require more postural control to prevent and reduce functional bindings and decrease involuntary movements medicine used to treat bv purchase 300 mg combivir free shipping. Along with this symptoms throat cancer generic combivir 300mg line, the sensory aspect is reinforced to provide better input to these stimuli, facilitating the integration and maturation of the systems involved, promoting a favorable adaptive response. Activities are conducted using vestibular and propioceptive sensations and promoting the development of righting and equilibrium reactions, with synergies to promote the organization of movement in relation to body and space (Ayres, 2006). It is also important to generate patterns of controlled and rhythmic breathing, as this has great impact on the voluntary control of movements and spoken language. At this stage, play is the main occupation of the child, which develops through social, emotional, cognitive, sensory, and motor functions. From this, it is essential that play is constantly referred to within the therapeutic activity and according to the therapy goals. Games should also be selected according to the abilities and interests of children, looking to present interesting challenges in order to promote the interest necessary to generate action. The relevance is focused in one punctual aspect: learning will occur to the extent that the activity has both significance and success for the child (Maturana, 2007). Some children will require external support such as furniture, orthotic or adaptation, but these are mostly transitory. In relation to postural control: the child that has interest and contact with the environment initiates movements to go out against gravity spontaneously, developing near-normal patterns. Progressively the child should be dominating higher positions and perform activities according to age. The therapist must accompany this process based on the sequences of normal development, safeguarding that the child does not use fixed resources by setting in abnormal postural patterns learned as functional. Treatment should be focused on correct and facilitate normal motor chain repetition reinforced by activities that bring success in a functional way. From a sensory point of view, treatment should include propioceptive and vestibular elements in order to stimulate the harmonious development of the movements. It is important to address the sitting posture as this is often used for play and influence the stability of hand function. If the child is seated early you may have the need for proximal postural fixation to stabilize the pelvis and trunk, making the transfer of weight and the degrees of freedom more difficult, limiting the possibility of developing movements in different planes which establish harmonic synergy for space exploration. In relation to the role of hands: the function of the hands is largely determined by a stable axial and proximal control, reason why it should be offered a work setting that provide adequate support for the position and sensory registration. In relation to the development of grips you can see a greater mastery of the gross grips, making it difficult or delayed acquisition of fine grips and digital dissociation. To promote the sound development, the child should experience tactile and propioceptive sensation in different games in two motor ways, globally and manipulative. This provides information on weight, texture, shape and size, which determines the progressive development of manual skills necessary for a variety of grasps, dissociated intermediate ranges and movements that will facilitate the execution of increasingly complex tasks according to age of development. The need of proximal fixation to reach stability and distal control needs to be avoided. This fixation reduces the degree of freedom of movement in space of upper extremities. Therefore, it is recommended that activities involving the use of hands are performed in a sitting position. The sitting position should include a stable chair with a rigid seat base and a table with cutout appropriate to the child’s size in order to provide stability to the forearms. For this age group and level it is suggested to postpone the use of orthotics in order to facilitate normal development. Be mindful not to encourage postural proximal fixation, but provide stability and assistance with some element of temporary external support. In relation to the activities of daily living: To carry out these tasks it should be considered to place the child in a stable position that allows him to have better resources to perform these activities. It is important that the family favors the development of activities as self-feeding, hygiene and clothing according to their age and thereafter provide environmental support with elements or adaptations to facilitate appropriate and successful implementation. Do not lose of sight that the difficulties in proximal stability and involuntary movements require to modify the pattern and sequence of execution to accomplish the task, since most of the movements’ performed to do these tasks require to go out against gravity which increases involuntary movements. It is suggested that during feeding, forearms are flat on a surface permanently; preventing that the elbow loses contact with the surface, thereby decreasing the involuntary movements. Along with this, if necessary, provide a thickened spoon and always give an indication of moving the head toward the spoon. In these activities the child may need adult assistance or elements that give stability to the plate like an antiskid or an adapted tray. As for hygiene and clothing the child must be an active participant in this routine, to internalize and reinforce appropriate sequences and energy efficiency. It is important to remember the age appropriate tasks watching runtimes to support achievement in the everyday as functional. Also you need to consider the necessary changes in terms of access, items available in the space, utensils and/or some element of temporary or permanent support or adaptation to facilitate the task. In this age self-care activities take on greater relevance with the gain of progressive independence in regards to the activities of basic daily life (Mulligan, 2006). In relation to school activities: It is recommended that this group of children start their schooling in regular school system of selection. Sometimes you need professional support to adapt specific elements related to specific subjects and tasks that require more accuracy or quality of execution. It may also be useful to assess if the furniture provides suitable positions favoring a proper execution of tasks, offering suggestions when necessary. Ages 6 and older Treatment in this group has a profile of progressively making a difference in the development of autonomy, independence and community involvement. After 12 years of age, the self-management of elements of support that foster a better occupational performance are well established. Dystonia and Rehabilitation in Children 127 In relation to the position: At this point it is important to constantly reassess all aspects of the postural adjustment because as growth implies a reorganization of motor schemes, were compensations or patterns may appear abnormal but, in most cases these are temporary. It must be safeguarded that these are not made permanent, damaging in a long-term the postural control and functional performance. In relation to hand function: Insofar as the child progresses through the school system, increasing demands will require greater demands on the quality and speed of execution, which could lead to a decrease in occupational performance, “both given” by the more demanding task and the stress. Assess and define strategies to optimize performance and in some cases it might be required the use of accommodations, furniture and technical assistance. The possible difficulties that might occur should be evaluated and corrected to avoid a significant detriment to the functional performance that has already being achieved. In periods of high growth they may become unstable, so it is recommended to reevaluate constants gait pattern to intervene therapeutically if the case requires so. In relation to activities of daily living: A child this age should increase the autonomy and independence according to age levels in activities of basic daily life, expanding progressively toward the instrumental activities. It must be constantly evaluated to decrease the third-party assistance, providing accommodations or modifications conducive to the attainment of independence. In the instrumental activities daily living it is suggested to increase tasks and responsibilities of intra domiciliary in addition to provide spaces for an active community participation, including documents management, money use, transportation and occupational activities, all age appropriate. In some cases these activities require therapeutic support and training to habituation, as well as to provide strategies, social skills and safety for a satisfactory performance. In relation to school activities: At this point they may demonstrate difficulties in relation to the time of execution, specifically in terms of writing. It is suggested to check if the furniture and tools are providing stability to optimize performance. In many cases, it is required to use support systems or alternative technologies that facilitate the execution of the task. Children older than twelve years should be identifying skills and interests to focus on alternative vocational and employment preferences that must be consistent with the real possibilities of the young. Ages 0 to 6 year this group of children presents clinical signs that can be seen early by a professional in the area. Treatment should be approached from models such as neurodevelopmental, sensory integration, behavioral and cognitive rehabilitation. From early stages when the child tries out against gravity, compensation and abnormal patterns emerge in response to the lack of control and axial synergies. In some cases we observe prolonged primitive reflexes that can be used as a functional resource, transforming it into a learned pattern that is pathological. It becomes important that the development of low postures should take special care and attention as it is on this stage when they begin to strengthen postural and proximal fixation. Managing the child that is less than one year old provides a postural control with elements or implements that help the organization in space, is important to achieve synergies and midline line which are precursors of visual monitoring and of the use of hands. In children over one year, in addition to the above, it begins to favor the functional activity of higher positions such as sitting and bipedal. Parallel to this, it is important to provide vestibular and propioceptive sensory input to enhance and promote afferential information to organize properly a functional motor and adaptive response. Efforts must be placed on patterns of controlled and rhythmic breathing to organize movements to facilitate and promote oral language. In the early stages this work is suggested by the mother who provides rhythmic breathing patterns, after this, the child should work this voluntarily or therapy could help to increase the quality of movement. In children older than three years, gross and fine motor demands become more complex, so the chances of feeling frustration or anxiety increases, making even more difficult the control of movement. This requires special attention when treating and choosing the activity and postural control support which needs to be both static and dynamic. Play and school activities are the main occupation of the child, which develops through social, emotional, cognitive, sensory and motor functions. The therapist must reconcile this with the selected therapeutic activity, not to mention that an activity generates significant and successful learning. Also at this stage the child enters a school system, which sometimes requires guidance or counseling in handling furniture and specific elements of technical assistance. In relation to postural control: In the early stages environmental elements must be conducive to proper posture and the ability to explore spontaneously. Supine flexion should be favored, using elements of containment that provide slight bend of the head and pelvis in order to provide a midline upper extremities, visual and abdominal activity. In prone, use a wedge to allow the right use of forearms or arm support on the surface to weight bearing and allow synergies of shoulder girdle, neck and head. Avoid a pattern of abnormal extension or hyperextension of the neck to be a precursor to every action. Often when turning there is a tendency to one side only and initiated from the head in hyperextension. In this case it will be necessary to facilitate synergies and dissociation in lateral planes. Dystonia and Rehabilitation in Children 129 In managing the sitting posture observe if the overall patterns are initiated from the head and/or pelvis, as this will be a critical control point to consider for the functional use of this position. In the case that the movement originates at the head, descending tactile and propioceptive information must be submitted in the sterna, to stimulate flexor muscles. In the event of involuntary movement generated in the pelvis, hip flexion facilitated greater than 90 degrees is required, in order to shift the weight to this area and reduce the chances of making an involuntary extensor pattern. In children less than one year sitting posture will be fully assisted given that the head and trunk control are still developing. Until the extent that the child is about three years old the control of head and trunk stability improves, but still continues to require assistance. There is instability due to weak righting reactions, slow or nonexistent, in addition to the predominance of the sagital plane flexion and extension patterns in total ranges. This makes more difficult the postural automatic control and intermediate ranges needed to maintain a stable sitting posture. It is important to consider providing a strong support level to promote sciatic propioceptive information at various levels to facilitate the automatic postural control. The use of postural seating made for each child ensures good posture avoiding that the child resort to fixation to stabilize posture against gravity. Along with this, the feet should also be in contact with a surface to provide support and control. On the other hand, although sometimes the child can sit independently at times on a bench, the child will lose stability when needed to go out and try different planes of motion or when using upper extremities for functional activity. However as a therapeutic target it will be beneficial to consider, because it is related to the axial control and it can provide lower assistance in postural and lower demand from the upper extremities function, or conversely if the goal is to increase functionality, further assist hands posture will be required. As for four points’ posture, crawling and transition to bipedal, the child will require great assistance as these positions involve transitions and intermediate ranges which should be assisted or facilitated by the therapist. For this, you can use external support elements to organize the space both physically and visually. Subsequently, the bipedal posture becomes important and can make an assisted start with some gait trainer with brachial support adaptation. In upper body it is recommended the support in the forearm on a surface as a tray or table with cutout in order to provide information at the proximal and shoulder girdle to stimulate axial and head control. This provides visual information regarding body position in space and promotes greater organization and global control. At the level of the pelvis it is helpful to use a cushion of sand to provide weight and more stability information to the seat bones, reducing the involuntary movements at this level. The use of compressive clothing must be evaluated for treatment and in some children may be useful regulating the tone and decreasing the degrees of freedom giving stability to the pelvic girdle, providing axial and proximal control (Rannie, 2005; Allen, 1997). It must be anticipated and address early the proximal fixations made by the child when looking for proximal stability and distal control. Subsequently this generates that the child will choose the upper extremity with less difficulties to perform the tasks, and the other extremity will be used as a postural fixation, which in the long term, will reduce the function and generate an asymmetry in the trunk and shoulder girdle producing postural scoliosis as a result of maintaining this position. Given the above, to facilitate the manual functionality it should be considered to provide axial stability to the pelvic girdle as a basis for proximal control. The greater functional requirement involving upper extremities movements in space at a proximal level and distal level as well as manual dexterity will require more support or postural control. This is why, efforts should consider pelvic and trunk stability by providing a stable sitting posture as a basis to support the role of hands in different planes in space. The use of tray or table with cutout helps control the movement of upper limbs when supporting the forearm.

Rickettsias in natural conditions are found in mammals and blood-sucking arthropods symptoms 8 weeks pregnant buy combivir australia. This tick has wide distribution in Africa and is present on several Caribbean islands treatment renal cell carcinoma discount combivir 300 mg fast delivery. Both wild and cultured Atlantic salmon are susceptible to infection medicine hat alberta canada best purchase combivir, as are brown trout (Salmo trutta) medicine for anxiety buy combivir 300 mg cheap, rainbow trout (Oncorhynchus mykiss) and herring treatment 2nd degree burn cheap combivir online. Recommended precautions include incineration of fish treatment 4 anti-aging effective 300mg combivir, tissues, blood and materials (gloves, laboratory coats, etc. General principles of laboratory safety should be practiced in handling and processing fish samples for diagnostic or investigative studies. Containment Recommendations Lumpy skin disease is considered a foreign animal disease in the United States. The disease primarily affects many poorly adapted species of Artiodactyla that suffer very high case mortality (>95%) but low case morbidity (<7%). The disease cannot be transmitted by natural means from one clinically susceptible host to another, because there is essentially no cell free virus in tissues or secretions of diseased animals. Infectivity in blood and tissues of affected animals is generally associated with viable lymphoid cells. The virus can be easily inactivated by wiping down surfaces with common disinfectants (such as bleach and sodium hypochlorite) and by autoclaving virus-contaminated materials. Clinical signs included stillborn, deformed, mummified piglets and a drop in the farrowing rate. A serological survey of fruit bats living near the swine operation revealed the presence of antibodies to MenV. Fruit bats are considered to be the natural host of the virus and their proximity to the affected premises led to an incidental infection in the pig 33,34 population. Other members of this family include Hendra virus, Nipah virus and Tioman virus of which Hendra and Nipah have been found to be fruit bat-associated. This virus was 385 Appendix D isolated from stillborn piglets from a single outbreak of reproductive disease in a commercial swine operation in New South Wales, Australia in 1997. Occupational Infections There was serological evidence of MenV infection in two people that had close contact with infected pigs on the affected premises. They demonstrated clinical signs similar to those seen with influenza such as chills, fever, drenching sweats, headache and rash. Containment Recommendations MenV is considered cause of a foreign animal disease in the United States and is a human pathogen. The bio-containment requirements for working with a particular strain are based on the virulence of the virus as determined by chicken inoculation and more recently by determination of amino acid sequence of the 35 fusion protein cleavage site (as defined by the World Organization for Animal Health). Natural transmission among birds 36,37 occurs by aerosol inhalation or by consumption of contaminated feed or water. All strains are readily propagated in embryonated chicken eggs and a variety of avian and mammalian cell cultures although special additives may be required to propagate the low virulence 35-37 (lentogenic) viruses in some cell types. Occupational Infections the most common infection is a self-limiting conjunctivitis with tearing and pain that develops within 24 hours of an eye exposure by aerosol, splash of infective fluids, or eye contact with contaminated hands. Laboratory workers should have no contact with susceptible hosts for five days after working with the agent. All rules concerning the possession, storage, use, and transfer of select agents apply. The virus has particular affinity for lymphoid tissues and epithelial tissue of the gastrointestinal and respiratory tracts, causing high fever, diphtheritic oral plaques, proliferative lip lesions, diarrhea, dehydration, pneumonia and death. In susceptible 39 populations morbidity is commonly 90% and mortality 50-80%, but can reach 100%. The virus is environmentally fragile and requires close direct contact for transmission. It is characterized by fever, oral erosions, diarrhea, lymphoid necrosis and high mortality. The disease is present in the Indian subcontinent, Near East and sub-Saharan Africa including Kenya and Somalia. It is immunologically related to canine distemper virus, human measles virus, peste pes petits ruminants virus, and marine mammal morbilliviruses. Following natural exposure, the incubation period ranges from 3 to 15 days but is usually 4 to 5 days. Containment Recommendations the virus is considered cause of a foreign animal disease in the United States. The virus can cause infection experimentally by intravenous, intradermal, intranasal, or subcutaneous inoculation. Containment Recommendations these viruses are considered cause of a foreign animal disease in the United States. Infections have occurred in common and koi carp (Cyprinus carpio), grass carp (Crenopharyngodon idellus), silver carp (Hypophthalmichthys molitix), bighead (Aristichthys nobilis), cruian carp (Carassius carassius), goldfish (C. Long indigenous to Europe, the Middle East and Asia, the disease was reported recently in South and North America. That year the virus was detected in fish in several lakes and rivers in Wisconsin, including the Mississippi River. Liver, kidney, spleen, gill and brain are the primary organs containing the virus 48 during infection. It is surmised that horizontal transmission occurs when waterborne virus enters through the gills. Once the virus is established in a pond or farm it may be difficult to eradicate without 25,28,49 destruction of all fish at the farm. Recommendations for preventing the disease and spread of disease include the use of a water source free of virus, disinfection of eggs and equipment, and proper disposal of dead fish. Direct and indirect contacts of infected materials, contaminated laboratory surfaces, and accidental autoinoculation, are the primary hazards to laboratory personnel. Biosecurity in aquaculture production systems: exclusion of pathogens and other undesirables. International response to infectious salmon anemia: prevention, control and eradication. In: Manual of standards for diagnostic tests and vaccines for terrestrial animals: mammals, birds and bees. Characteristics of a virus causing a pox disease in sheep and goats in Kenya, with observations on the epidemiology and control. Transmission of exotic fish viruses: the relative risks of wild and cultured bait. Department of Agriculture Animal and Plant Health Inspection Service Veterinary Services, National Center for Import and Export 4700 River Road, Unit #40 Riverdale, Maryland 20737-1231 Telephone: (301) 734 5960 Fax: (301) 734-3256 Internet: Department of Agriculture Animal and Plant Health Inspection Service Plant Protection and Quarantine, Permits, Agricultural Bioterrorism 4700 River Road, Unit Riverdale, Maryland 20737-1231 Telephone: (301) 734-8896. Arthropods included are those that transmit pathogens; however, those arthropods that cause myiasis, infestation, biting, and stinging are not included. A project of the American Committee of Medical Entomology and American Society of Tropical Medicine and Hygiene. The Agricultural Bioterrorism Protection Act of 2002, Subtitle B of Public Law 107-188 (7 U. These Acts require the establishment of a national database of registered entities, and set criminal penalties for failing to comply with the requirements of the Acts. The regulations set out a procedure for excluding an attenuated strain of a select agent or toxin and exemptions for certain products and for select agents or toxins identified in specimens presented for diagnosis, verification, or proficiency testing. The regulations also contain requirements to ensure that the select agents and toxins are handled safely and secured against unauthorized access, theft, loss, or release. Many pests, such as flies and cockroaches, can mechanically transmit disease pathogens and compromise the research environment. Even the presence of innocuous insects can contribute to the perception of unsanitary conditions. The most common approach to pest control has been the application of pesticides, either as a preventive or remedial measure. Pesticides can be effective and may be necessary as a corrective measure, but they have limited long-term effect when used alone. Pesticides also can contaminate the research environment through pesticide drift and volatilization. To control pests and minimize the use of pesticides, it is necessary to employ a comprehensive program approach that integrates housekeeping, maintenance, and pest control services. This provides an opportunity to incorporate features that help exclude pests, minimize pest habitat, and promote proper sanitation in order to reduce future corrections that can disrupt research operations. Sanitation and Facility Maintenance Many pest problems can be prevented or corrected by ensuring proper sanitation, reducing clutter and pest habitat, and by performing repairs that exclude pests. Records of structural deficiencies and housekeeping conditions should be maintained to track problems and determine if corrective actions have been completed in a timely manner and were effective. Reports communicated verbally and in writing concerning pest activity and improvement recommendations for personnel practices and facility conditions should be provided to the designated personnel. Pest Control with Pesticides 401 Appendix G Preventive applications of pesticides should be discouraged, and treatments should be restricted to areas of known pest activity. Pest management personnel should be licensed and certified by the appropriate regulatory agency. There are reports of infection of laboratory workers 1 handling primary rhesus monkey kidney cells, and the bloodborne pathogen risks from 2,3 working with primary human cells, tissues and body fluids are widely recognized. Procedures have also been published to reduce contamination of cell cultures with 5,6 microorganisms. Tumorigenic 8 human cells also are potential hazards as a result of self-inoculation. There has been one 9 reported case of development of a tumor from an accidental needle-stick. Recommended Practices Each institution should conduct a risk assessment based on the origin of the cells or tissues (species and tissue type), as well as the source (recently isolated or well characterized). All laboratory staff working with human cells and tissues should be enrolled in an occupational medicine program specific for bloodborne pathogens and should work under the policies and guidelines established 4 by the institution’s Exposure Control Plan. Laboratory staff working with human cells and tissues should provide a baseline serum sample, be offered hepatitis B immunization, and be evaluated by a health care professional following an exposure incident. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to healthcare and public safety workers. Toxins do not replicate, are not infectious, and are difficult to transmit mechanically or manually from person to person. Many commonly employed toxins have very low volatility and, especially in the case of protein toxins, are relatively unstable in the environment; these characteristics further limit the spread of toxins. Toxins can be handled using established general guidelines for toxic or highly toxic chemicals with the incorporation of additional safety and security measures based 3,4 upon a risk assessment for each specific laboratory operation. The main laboratory risks are accidental exposure by direct contamination of mouth, eyes or other mucous membranes; by inadvertent aerosol generation; and by needle-sticks or other accidents that may compromise the normal barrier of the skin. The worker must be reliable and sufficiently adept at all required manipulations before being provided with toxin. A risk assessment should be conducted to develop safe operating procedures before undertaking laboratory operations with toxins; suggested “pre-operational 4 checklists” for working with toxins are available. For complex operations, it is recommended that new workers undergo supervised practice runs in which the exact laboratory procedures to be undertaken are rehearsed without active toxin. Likewise, animal safety practices must be considered for toxin work involving animals. The National Research Council has provided a review of prudent laboratory practices when handling toxic and highly toxic chemicals, including the development of chemical hygiene plans and guidelines for compliance with regulations governing occupational 5 safety and health, hazard communication, and environmental protection. An inventory control system should be in place to account for toxin use and disposition. If toxins are stored in the laboratory, containers should be sealed, labeled, and secured to ensure restricted access; refrigerators and other storage containers should be clearly labeled and provide contact information for trained, responsible laboratory staff. Engineering controls should be selected according to the risk assessment for each specific toxin operation. Operations that expose toxin solutions to vacuum or pressure, for example sterilization of toxin solutions by membrane filtration, should always be handled in this manner, and the operator should also use appropriate respiratory protection. The outside surfaces of containers and rotors should be routinely cleaned before each use to prevent contamination that may generate an aerosol. Only workers trained and experienced in handling animals should be permitted to conduct operations involving injection of toxin solutions using hollow-bore needles. Discarded needles/syringes and other sharps should be placed directly into properly labeled, puncture-resistant sharps containers, and decontaminated as soon as is practical. Glassware should be replaced with plastic for handling toxin solutions wherever practical to minimize the risk of cuts or abrasions from contaminated surfaces. Glass Pasteur pipettes are particularly dangerous for transferring toxin solutions and should be replaced with 407 disposable plastic pipettes. In specialized laboratories, the intentional, controlled generation of aerosols from toxin solutions may be undertaken to test antidotes or vaccines in experimental animals. These are extremely hazardous operations that should only be conducted after extensive validation of equipment and personnel, using non-toxic simulants. While removing exposed animals from the hoodline, and for required animal handling during the first 24 h after exposure, workers should take additional precautions, including wearing protective clothing. To minimize the risk of dry toxin generating a secondary aerosol, areas of animal skin or fur exposed to aerosols should be gently wiped with a damp cloth containing water or buffered cleaning solution before the animals are returned to holding areas. For high-risk operations involving dry forms of toxins, intentional aerosol formation, or the use of hollow-bore needles in conjunction with amounts of toxin estimated to be lethal for humans, consideration should be given to requiring the presence 7 of at least two knowledgeable individuals at all times in the laboratory.

Laboratory doors must be self-closing and have locks in accordance with the institutional policies treatment ind order combivir now. The laboratory must be separated from areas that are open to unrestricted traffc fow within the building acne natural treatment discount combivir 300 mg free shipping. A clothing change room (anteroom) may be included in the passageway between the two self-closing doors the treatment 2014 online 300mg combivir mastercard. Consideration should be given to the installation of seamless treatment 2nd degree burn order combivir us, sealed medicine abbreviations discount combivir 300 mg with amex, resilient or poured foors treatment action campaign cheap 300mg combivir overnight delivery, with integral cove bases. Walls should be constructed to produce a sealed smooth fnish that can be easily cleaned and decontaminated. Ceilings should be constructed, sealed, and fnished in the same general manner as walls. Decontamination of the entire laboratory should be considered when there has been gross contamination of the space, signifcant changes in laboratory usage, for major renovations, or maintenance shut downs. Selection of the appropriate materials and methods used to decontaminate the laboratory must be based on the risk assessment. Chairs used in laboratory work must be covered with a non-porous material that can be easily cleaned and decontaminated with appropriate disinfectant. This system must provide sustained directional airfow by drawing air into the laboratory from “clean” areas toward “potentially contaminated” areas. The laboratory shall be designed such that under failure conditions the airfow will not be reversed. A visual monitoring device, which confrms directional airfow, must be provided at the laboratory entry. The laboratory exhaust air must not re-circulate to any other area of the building. Enhanced environmental and personal protection may be required by the agent summary statement, risk assessment, or applicable local, state, or federal regulations. Biosafety Level 4 Biosafety Level 4 is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Laboratory staff must have specifc and thorough training in handling extremely hazardous infectious agents. Laboratory staff must understand the primary and secondary containment functions of standard and special practices, containment equipment, and laboratory design characteristics. The laboratory supervisor in accordance with institutional policies controls access to the laboratory. A Suit Laboratory—Personnel must wear a positive pressure supplied air protective suit. Use of needles and syringes or other sharp instruments should be restricted in the laboratory, except when there is no practical alternative. Decontaminate all wastes before removal from the laboratory by an effective and validated method. Therefore, all laboratory personnel and particularly women of childbearing age should be provided with information 46 Biosafety in Microbiological and Biomedical Laboratories regarding immune competence and conditions that may predispose them to infection. All persons entering the laboratory must be advised of the potential hazards and meet specifc entry requirements in accordance with institutional policies. Only persons whose presence in the facility or individual laboratory rooms is required for scientifc or support purposes are authorized to enter. All persons entering the laboratory must use laboratory clothing, including undergarments, pants, shirts, jumpsuits, shoes, and gloves (as appropriate). After the laboratory has been completely decontaminated and all infectious agents are secured, necessary staff may enter and exit without following the clothing change and shower requirements described above. Laboratory personnel and support staff must be provided appropriate occupational medical services including medical surveillance and available immunizations for agents handled or potentially present in the laboratory. An essential adjunct to such an occupational medical services system is the availability of a facility for the isolation and medical care of personnel with potential or known laboratory-acquired infections. The laboratory supervisor is responsible for ensuring that laboratory personnel: a. Receive appropriate training in the practices and operations specifc to the laboratory facility. Receive annual updates and additional training when procedural or policy changes occur. Removal of biological materials that are to remain in a viable or intact state from the laboratory must be transferred to a non-breakable, sealed primary container and then enclosed in a non-breakable, sealed secondary container. Laboratory equipment musts be routinely decontaminated, as well as after spills, splashes, or other potential contamination. Spills involving infectious materials must be contained, decontaminated, and cleaned up by appropriate professional staff, or others properly trained and equipped to work with infectious material. Equipment must be decontaminated using an effective and validated method before repair, maintenance, or removal from the laboratory. All incidents must be reported to the laboratory supervisor, institutional management and appropriate 48 Biosafety in Microbiological and Biomedical Laboratories laboratory personnel as defned in the laboratory biosafety manual. The doors of the autoclave or fumigation chamber are interlocked in a manner that prevents opening of the outer door unless the autoclave or fumigation chamber has been operated through a decontamination cycle. All equipment and supplies taken inside the laboratory must be decontaminated before removal from the laboratory. Daily inspections of essential containment and life support systems must be completed and documented before laboratory work is initiated to ensure that the laboratory is operating according to established parameters. These protocols must include plans for medical emergencies, facility malfunctions, fres, escape of animals within the laboratory, and other potential emergencies. All sharp edges on cabinet fnishes must be eliminated to reduce the potential for cuts and tears of gloves. Such materials should be centrifuged inside the cabinet using sealed rotor heads or centrifuge safety cups. Workers in the laboratory must wear protective laboratory clothing with a solid-front, such as tie-back or wrap-around gowns, scrub suits, or coveralls. Reusable clothing must be autoclaved prior to removal from the laboratory for laundering. Disposable gloves must be worn underneath cabinet gloves to protect the worker from exposure should a break or tear occur in a cabinet glove. All procedures must be conducted by personnel wearing a one-piece positive pressure supplied air suit. Workers must wear laboratory clothing, such as scrub suits, before entering the room used for donning positive pressure suits. All laboratory clothing must be removed in the dirty side change room before entering the personal shower. Inner disposable gloves must be worn to protect against break or tears in the outer suit gloves. Inner gloves must be removed and discarded in the inner change room prior to entering the personal shower. Decontamination of outer suit gloves is performed during laboratory operations to remove gross contamination and minimize further contamination of the laboratory. A double-door autoclave, dunk tank, fumigation chamber, or ventilated airlock must be provided at the containment barrier for the passage of materials, supplies, or equipment. Walls, foors, and ceilings of the laboratory must be constructed to form a sealed internal shell to facilitate fumigation and prohibit animal and insect intrusion. All penetrations in the internal shell of the laboratory and inner change room must be sealed. Drains in the laboratory foor (if present) must be connected directly to the liquid waste decontamination system. Laboratory furniture must be of simple construction, capable of supporting anticipated loading and uses. The supply and exhaust components of the ventilation system must be designed to maintain the laboratory at negative pressure to surrounding areas and provide differential pressure or directional airfow, as appropriate, between adjacent areas within the laboratory. A visual monitoring device must be installed near the clean change room so proper differential pressures within the laboratory may be verifed prior to entry. The air exhaust discharge must be located away from occupied spaces and building air intakes. Provisions to assure proper safety cabinet performance and air system operation must be verifed. Liquid effuents from cabinet room sinks, foor drains, autoclave chambers, and other sources within the cabinet room must be decontaminated by a proven method, preferably heat treatment, before being discharged to the sanitary sewer. The decontamination process for liquid wastes must be validated physically and biologically. Biological validation must be performed annually or more often if required by institutional policy. Effuents from showers and toilets may be discharged to the sanitary sewer without treatment. This bioseal must be durable and airtight and capable of 54 Biosafety in Microbiological and Biomedical Laboratories expansion and contraction. When feasible, autoclave decontamination processes should be designed so that unfltered air or steam exposed to infectious material cannot be released to the environment. Provisions for emergency communication and emergency access or egress must be developed and implemented. A chemical shower must be provided to decontaminate the surface of the positive pressure suit before the worker leaves the laboratory. In the event of an emergency exit or failure of the chemical shower system, a method for decontaminating positive pressure suits, such as a gravity fed supply of chemical disinfectant, is needed. A double-door autoclave, dunk tank, or fumigation chamber must be provided at the containment barrier for the passage of materials, supplies, or equipment in or out of the laboratory. Sinks inside the suit laboratory should be placed near procedure areas and be connected to the wastewater decontamination system. The internal surfaces of this shell must be resistant to chemicals used for cleaning and decontamination of the area. Chairs and other furniture must be covered with a non-porous material that can be easily decontaminated. The supply and exhaust components of the ventilation system must be designed to maintain the laboratory at negative pressure to surrounding areas and provide differential pressure or directional airfow as appropriate between adjacent areas within the laboratory. A double-door, pass through autoclave(s) must be provided for decontaminating materials passing out of the cabinet laboratory. Autoclaves that open outside of the laboratory must be sealed to the interior wall. Positioning the bioseal so that the equipment can be accessed and maintained from outside the laboratory is strongly recommended. In both instances, the institutional management must provide facilities, staff, and established practices that reasonably ensure appropriate levels of environmental quality, safety, security and care for the laboratory animal. In the animal room, the activities of the animals themselves can present unique hazards not found in standard microbiological laboratories. The co-application of Biosafety Levels and the Animal Biosafety Levels are determined by a protocol-driven risk assessment. These recommendations presuppose that laboratory animal facilities, operational practices, and quality of animal care meet applicable standards and regulations. Traffc fow that will minimize the risk of cross contamination should be incorporated into the facility design. Investigators that are inexperienced in conducting these types of experiments should seek help in designing their experiments from individuals who are experienced in this special work. Facility standards and practices for invertebrate vectors and hosts are not specifcally addressed in this section. The reader is referred to Appendix E for more information on the Arthropod Containment Guidelines. Animal Biosafety Level 1 Animal Biosafety Level 1 is suitable for work in animals involving well-characterized agents that are not known to cause disease in immunocompetent adult humans, and present minimal potential hazard to personnel and the environment. Special containment equipment or facility design may be required as determined by appropriate risk assessment. The supervisor must ensure that animal care, laboratory and support personnel receive appropriate training regarding their duties, animal husbandry procedures, potential hazards, manipulations of infectious agents, necessary precautions to prevent exposures, and hazard/ exposure evaluation procedures (physical hazards, splashes, aerosolization, etc. Personnel must receive annual updates and additional training when procedures or policies change. Identifcation of specifc infectious agents is recommended when more than one agent is being used within an animal room. Security-sensitive agent information should be posted in accordance with the institutional policy. All persons including facility personnel, service workers, and visitors are advised of the potential hazards (natural or research pathogens, allergens, etc. Persons must wash their hands after removing gloves, and before leaving the areas where infectious materials and/or animals are housed or are manipulated. Eye and face and respiratory protection should be used in rooms containing infected animals, as dictated by the risk assessment. Food must be stored outside of the laboratory in cabinets or refrigerators designed and used for this purpose. When applicable, laboratory supervisors should adopt improved engineering and work practice controls that reduce the risk of sharps injuries. Equipment and work surfaces are routinely decontaminated with an appropriate disinfectant after work with an infectious agent, and after any spills, splashes, or other overt contamination. Special containment devices or equipment may not be required as determined by appropriate risk assessment.

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