Scott D. Ganz, DMD

• Clinical Assistant Professor, Department of Restorative Dentistry
• University of Medicine and Dentistry of New Jersey
• Newark, NJ
• Prosthodontics, Maxillofacial Prosthetics &
• Implant Dentistry
• Fort Lee, New Jersey

Notably treatment 4 syphilis order cytotec now, studies of behavioral treatment have shown beneficial effects of intervention throughout the age range from preschool to adolescence symptoms precede an illness purchase cytotec once a day. At the same time symptoms gallstones buy generic cytotec 200mcg line, the literature is most abundant on elementary-aged children symptoms of anemia buy cheap cytotec 200 mcg line, and there is much more research with younger children than with adolescents medicine 7 years nigeria order cheap cytotec line, where more is needed (Smith medications like prozac cytotec 100 mcg sale, Waschbusch, Willoughby, & Evans, 2000). Studies have typically lasted a matter of months, with effects usually measured at treatment termination or after follow-up periods of a few months. The magnitude of effects is typically moderate to large, with within-subject designs yielding larger effects than between-group designs (Pelham & Fabiano, in press; Pelham, Wheeler, & Chronis, 1998). Positive effects were found regardless of comorbidity, and in some studies, the impact of parent training was greatest when comorbidities were present. Although most studies have focused on children between 6 and 12 years of age, studies have shown similar changes in both younger children. The majority of the dozens of studies have investigated relatively intensive programs. Many of the studies described above have included daily seatwork productivity and accuracy as outcomes, and the impact of the classroom management programs on those variables is well established (DuPaul & Eckert, 1997; Fabiano, Pelham, Coles, et al. However, these studies focus on acute daily functioning rather than on achievement measured over time. Beyond the utility of contingency management to improve daily seatwork productivity/accuracy, firm conclusions about the efficacy of academic interventions for this population must be tempered until findings from single-subject design studies are replicated with Report of the Working Group on Psychotropic Medications 40 larger samples in the context of controlled experimental trials, and academic achievement is employed as an outcome. Peer Interventions Interventions focused on peer relationships have been less well studied than parent training and classroom interventions. These interventions focus on teaching social skills, social problem solving, and behavioral competencies. Typically, these programs are not provided as stand-alone programs, but integrate parent training. There is preliminary evidence from a small number of studies that weekly social skills groups might add incrementally to the effects of school-based and home-based interventions. There is considerable evidence that an intensive package delivered in a summer camp setting that includes social skills training, a reward and cost system, group practice, and instruction in sports skills and team membership reliably produces medium to large acute effects (Chronis et al. Studies of these intensive summer interventions have included children ranging from 5 to 14 years of age. Report of the Working Group on Psychotropic Medications 41 Strength of Evidence for Psychosocial Interventions Numerous studies summarized in several reviews have shown that effect sizes for psychosocial interventions are in the moderate to large range, depending on the type of study designs. The DuPaul and Eckert meta-analysis focused on school-based studies, Lundahl et al. Effect sizes in crossover designs are computed with a different metric and are rarely included in traditional meta-analyses. When analyzed, they reveal a very large impact of behavioral treatment, yielding considerably larger effect sizes compared with those in between-group studies. Finally, effect sizes in studies with single-subject designs are even larger in meta analyses that have included them. As discussed below, all of these effects are in the same range as those that have been summarized in reviews of stimulant medication. The only review that has separated the effects of behavior modification by target domain (Fabiano, Pelham, Coles, et al. When academic achievement has been assessed, there are few studies that have lasted enough time to measure achievement. As with medication, behavioral treatments have had little impact on long-term academic achievement. When acute measures of academic functioning are assessed, effect sizes are in the moderate to large range for seatwork productivity but in the small range for achievement measures. The first, third, and fourth of these limitations apply to stimulant medications as well (see discussion below). Given that both stimulant medications and behavioral treatments have limitations, many professionals believe that combined interventions are most effective and should be routinely employed. Stimulant medication use has grown steadily throughout the last two decades, particularly among preschool and secondary school populations (Olfson, Marcus, Weissman, & Jensen, 2002; Robison, Sclar, Skaer, & Galin, 1999). The average duration of medication use is between 2 and 7 years depending upon the age of the child (Safer & Zito, 2000). Numerous empirical studies have documented the short-term behavioral effects of stimulants, including improvements in attention and task completion with concomitant reductions in Report of the Working Group on Psychotropic Medications 43 impulsivity, disruptive behavior, and, in some cases, aggression. However, the number of studies is small, and the dependent measure assessed has typically been parent or clinician symptom ratings, as opposed to the large range of objective measures and hundreds more studies of stimulant effects. The approved label for atomoxetine has recently been modified and carries warnings of potential drug-related problems in aggressive behavior, suicidality, and liver toxicity (U. These nonstimulant compounds do not appear to be as effective as stimulants and have comparable (or higher) risk of side effects, and, therefore, are considered second-choice pharmacological treatments (Wigal et al. Guanfacine is an antihypertensive agent that Report of the Working Group on Psychotropic Medications 44 appears to have similar behavioral effects to clonidine but has not been evaluated extensively with controlled trials (Cohn & Caliendo, 1997). Studies have investigated various antidepressant medications, including tricyclics (Spencer, Biederman, & Wilens, 1998; Spencer, Biederman, Wilens, Steingard, & Geist, 1993), and bupropion (Casat, Pleasants, Schroeder, & Parker, 1989; Conners et al. Although it has been suggested that the combination of atomoxetine and a stimulant also may lead to better symptomatic improvement in children resistant to monotherapy (T. Brown, 2004), this combination has not been investigated in any controlled trial to date. Further, there are no data regarding the safety of this combination of medications. There are scant data regarding polypharmacy in general, with this population, despite its widespread use. For all Report of the Working Group on Psychotropic Medications 45 nonstimulant medications, short-term safety data are also lacking. In addition, as with behavior therapy, stimulants do not normalize functioning of most children even acutely. Strength of Evidence For the stimulants (primarily methylphenidate), effect sizes for behavior. Effect sizes for measures of academic productivity are low to moderate and are in the zero range for academic achievement. The overall effect size for stimulant treatment is in the moderate range, with larger effects associated with teacher and parent ratings than for direct observations and lab measures (Conners, 2002). Effect sizes for atomoxetine are in the moderate to large range on parent/clinician symptom ratings, while the magnitude of effect for other compounds. Side Effects Potential adverse side effects of stimulants include insomnia, appetite reduction, and irritability (Connor & Barkley, 2006), as well as growth suppression (approx. Acute adverse effects typically diminish with a reduction in dosage; growth suppression can be attenuated with twice daily vs. Stimulant medications do not appear to exacerbate tic disorders (Gadow, Sverd, Sprafkin, Nolan, & Ezor, 1995; Kurlan, et al. Regarding risk for substance abuse, findings have been equivocal, with approximately equal numbers of studies showing no, heightened, and reduced risk (S. Anderson, Arvanitogiannis, Pliakas, LeBlanc, & Carlezon, 2002; Barkley, Fischer, Smallish, & Fletcher, 2003; Biederman et al. For example, atomoxetine can lead to stomach aches, nausea, decreased appetite, and failure to gain weight (Christman, Fermo, Markowitz, 2004). Possible side effects associated with combined medication protocols have not been investigated extensively. Because many studies have shown that beneficial stimulant effects are maximized at much lower doses in the presence of concurrent behavioral treatment. Combined Interventions Studies of combined interventions have the same characteristics as those that have evaluated behavior therapy alone. Thus, interventions have been conducted in controlled Report of the Working Group on Psychotropic Medications 47 settings such as summer treatment programs and special classroom settings (Abramowitz et al. In a prototypic finding in a controlled setting, Carlson and colleagues (Carlson et al. Notably, when high-intensity doses of either medication or behavior therapy are used, there is often little evidence for the value of combined interventions. The between-group studies in natural settings also show evidence of combined treatment effects, but the number of studies is smaller, and their effects are somewhat smaller than in controlled settings relative to medication alone. Further, secondary analyses showed clearly that combined treatment was superior to medication alone on almost every dependent measure, as well as for (a) comorbid children, (b) impairments in multiple domains (vs. Combined treatment effects are in the moderate effect Report of the Working Group on Psychotropic Medications 49 size range for daily measures of academic seatwork productivity. As would be expected given the lack of evidence for benefit on long-term achievement of the two components, there is no evidence to date of combined treatment effects on academic achievement. Recent studies indicate that there may be important differences in treatment acceptability and response between racial and ethnic groups, especially in relation to the use of stimulant medication. For example, African American children may experience higher blood pressure with stimulant treatment (R. This pattern of differential treatment use may be related to racial differences in the acceptability of pharmacological treatment approaches as well as disparities in insurance coverage as a function of socioeconomic status. Other treatment studies have also shown that behavioral treatments are effective independent of ethnicity. Both forms of treatment have acute limitations that are addressed in Report of the Working Group on Psychotropic Medications 51 part in combination therapies, giving rise to the popularity of multimodal treatments. Though some have argued that the rewards that are integral to behavior modification may have an iatrogenic effect on intrinsic motivation (Akin-Little, Eckert, Lovett, & Little, 2004), careful analysis of this issue fails to support this alleged side effect (also see discussion below regarding deviancy training in group settings). There is no evidence that stimulants produce effects that maintain over years, generalize after medication is stopped, and/or alter long-term outcomes of treated individuals. There is growing concern that growth suppression may be an iatrogenic effect of stimulants that will reliably accompany long-term use. As discussed above, very little is known about the long-term risks of stimulants in other domains. At the 2-year follow-up, children in combined treatment had the same outcomes as those in behavioral treatment alone, and they had growth suppression, as did the medicated children (albeit less because of lower doses). There is some indication from a single short-term study that such an outcome might be attainable with very low dosages of stimulants (Pelham, Burrows-MacLean, et al. This would be particularly true for antidepressants, which have lower efficacy and greater side effects than stimulants. Alternatively, should behavior modification be employed first, and if so, how should the components (parent training, school intervention, and peer intervention) be sequenced How long should behavior Report of the Working Group on Psychotropic Medications 53 modification be tried and at what intensity before medication is added Might a behavioral treatment-first sequence result in lower societal use of stimulants or lower doses with fewer side effects when employed Or should the two major modalities begin simultaneously so that all children receive both modalities Which components can be time limited, and how does treatment need to be modified as children move through different developmental stages Given the minimal impact of medication and psychosocial interventions on academic achievement, particularly over the long-term, what academic interventions are efficacious with this population, and how can these be delivered feasibly along with behavioral strategies in school settings These are questions practitioners and parents face on a daily basis that beg answers. Home-based behavior modification typically involves parents receiving training in both antecedent-based. Similarly, school-based behavior modification approaches include the use of contingent teacher praise and/or reprimands, token reinforcement, response cost, time out from positive reinforcement, and self-management. Most school-based interventions are implemented directly by classroom teachers; however, contingencies can also be delivered by peers (Cunningham & Cunningham, 1998) and/or parents. Home and school-based contingency management interventions are associated with significant improvements in compliance and concomitant reductions in aggression and disruptive behavior (Walker, Colvin, & Ramsey, 1995; Webster-Stratton, 1994), although these effects are less pronounced in adolescents, and generalization of effects across settings and time is limited. Behavioral parent training is associated with a medium effect size for reduction of externalizing behaviors (Maughan, Christiansen, Jenson, Olympia, & Clark, 2005). Multisystemic treatment provides problem-focused treatment within families and also supports family members in managing the interconnected systems of family, peer, neighborhood, and school in order to reduce risks.

Dentists cite several reasons for not participating in Medicaid; the most common are low Medicaid Sixty to 70 percent of dental care for low-income payment rates symptoms restless leg syndrome cytotec 100 mcg, the administrative burden symptoms menopause cytotec 100 mcg online, and populations is provided in private practice settings symptoms mononucleosis cheap cytotec 100 mcg. Increasing which can be sponsored by federal medicine 7767 buy cytotec uk, state medications at 8 weeks pregnant purchase cytotec from india, or local Medicaid payment rates to a level where payments governments (including federally qualifed health are high enough to cover overhead expenses has centers) medicine 93 5298 discount cytotec online, voluntary organizations, non-proft and been found to increase provider participation, but public hospitals, and dental schools and residency is not a solution on its own. Some states be accompanied by administrative reforms and and communities are working to increase access partnerships with state dental associations and to dental services, particularly for underserved individual dentists (Borchgrevink et al. In one pilot program in Virginia referred patients with study, Medicaid enrollees without dental benefts dental pain from the emergency department to were nearly three times as likely to have unmet an in-hospital dental clinic, reducing the number dental needs compared to those whose Medicaid of dental patients with repeat visits to the coverage included dental benefts, and they were emergency department by 66 percent in the frst one-third as likely to get annual dental checkups year (Chesser 2014). One information and assurances that patients would study found that emergency department dental be seen quickly if they called the dental providers visits by Medicaid benefciaries increased by 23 the next day if the emergency department visit was percent several months after California eliminated after hours (Chang 2013). A Maryland study conducted 15 years after the California study had similar results, seeing an increase of 22 percent in emergency department dental Efforts to Improve Access visits after Medicaid adult dental benefts were to Dental Services eliminated (Cohen et al. However, another Maryland study found that Medicaid spending Like other forms of health coverage, dental for emergency department dental care for adults coverage increases access to care, and most rose by only 8 percent after the state eliminated low-income adults with dental coverage receive Medicaid dental benefts (Mullins et al. Federal law does A national study found a small increase in the not mandate dental coverage for adult Medicaid number of Medicaid adult emergency dental claims benefciaries, so despite the strong link between at emergency departments over a period of seven oral health and physical health and the signifcant years, during which time several states reduced burden of oral disease among low socioeconomic or eliminated Medicaid dental benefts (Lee et al. Even within department use, when adult dental benefts in states, Medicaid dental benefts can vary from one Medicaid are scaled back, community health year to the next, making it difcult for benefciaries centers have reported not having enough capacity and their providers to know what services are covered. California law allows dental resulting in lost opportunities for prevention and hygienists to perform certain procedures early treatment. Examples of innovative projects include Medicaid enrollees through provider the following: incentives. Minnesota has enacted a 1 Originally the requirement to provide comprehensive program to create a new type of dental dental services only pertained to children enrolled in professional, called a dental therapist. In particular, we plan to analyze data on enrollee use of the emergency room for dental services and how such References service use relates to state coverage policies. An examination of periodontal treatment, dental care, and pregnancy outcomes in an insured population in the United States. BadgerCare Plus and Medicaid, Dental, Covered and Noncovered California Medi-Cal Dental Program. Academy for State Health Policy and Georgetown University Covered Services Comparison Chart. State case studies: 1115 of the Social Security Act Medicaid Demonstration: improving access to dental care for the underserved. Journal of the (Project Number 11-W-00289/5) and Iowa Marketplace American Dental Association 127, no. Foundation and Health Research & Educational Trust Employer Health Benefts 2014 Annual Survey. Presentation before the Joint Commission on Health Care, Commonwealth of Detman, L. Exploring dental care misconceptions and barriers in gov/3%20Adult%20Oral%20Health%20Pres%20fnal. Indiana Medicaid National and state-level projections of dentists and dental for Members. Children and oral health: Assessing needs, coverage, One Patient at a Time Conference, May 10, 2014, Indianapolis, and access. Oral health and low-income nonelderly adults: A review dental visits and expenditures Commonwealth of Massachusetts MassHealth Kentucky Cabinet for Health and Family Services, Provider Manual Series, Subchapter 6, Service Codes. Medicaid coverage of adult dental periodontal diseases and systemic diseases: A review of the services. Journal of the American Dental Visiting the emergency department for dental problems: Association 146, no. Early impacts of dental therapists in Minnesota: highest ever among children, continues to decline among Report to the Minnesota Legislature 2014. State of Nebraska loan repayment program for rural health Montana Department of Public Health and Human Services. Dental Services of State Health Policy 27th Annual State Health Policy Coverage Policy. In biologic parameters, and pregnancy outcomes: a pilot the Medicaid resource book. CenteringPregnancySmiles: Implementation of a small group prenatal care model with oral health. Factors contributing to low use of dental services by low-income South Dakota Department of Social Services. Utah Medicaid Provider Manual: Dental, Oral Maxillofacial, and 44 June 2015 Chapter 2: Medicaid Coverage of Dental Benefits for Adults Washington Apple Health. Covered services include a limited problem focused examination of the oral cavity, required radiographs, complex oral surgical procedures such as treatment of maxillofacial fractures, administration of an appropriate anesthesia and the prescription of pain medication and antibiotics. The state contracts with Amerigroup Community Care, Peach State Health Plan, and WellCare health plans for Medicaid services and all three provide additional dental benefts for free to benefciaries, including oral exams, cleanings, and simple tooth removal. Adult dental benefts are restricted to a limited panel of services necessary for the control or relief of dental pain, elimination of infection of dental origin, management of trauma and/or treatment of acute injuries to teeth and supporting structures. However, three Medicaid managed care organizations operate in Kansas, and all three offer limited dental benefts as a value-added service. For example, covered services for an adult with a complaint of acute pain may include a problem-focused examination and radiographs to the extent needed to diagnose and document the need for the extraction, as well as needed to perform the extraction itself. Surgical tooth extraction must have medical need documented if not apparent on images of tooth. Allowable services include emergency dental treatment necessary to control bleeding, relieve pain and eliminate acute infection; preventative procedures required to prevent the imminent loss of teeth; the treatment of injuries to teeth or supporting structure; dentures and the cost of preparation and ftting; and routine procedures necessary to maintain good oral health. Nevertheless, certain emergency dental procedures are a least costly alternative to covered services outside of the dental program and can be reimbursed. Changes in the oral environment after placement of removable dentures in low caries risk patients Fumihiro Nakayama, Junko Tanaka and Masahiro Tanaka Department of Fixed Prosthodontics and Occlusion, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata-shi, Osaka 573-1121, Japan We did a follow-up investigation that examined changes over time in the oral environment of low caries risk patients after initial placement of removable prostheses. Denture and Dentate groups of aged subjects were followed up over time to track changes in their oral environ ment. Seven oral environment factors were selected that strongly correlate with caries risk, including unstimulated and stimulated salivary flow rate, unstimulated and stimulated sali vary buffering capacity, and oral bacteria (mutans streptococci, lactobacilli and Candida). We concluded that place ment of removable dentures changed low caries risk to high for the number of lactobacilli. Fu ture investigations should be done on preventive measures against the caries-inducing ef fect of denture placement. Many people lose teeth because of caries ses compared with those who had removable pros 3 and/or periodontal diseases. Although these studies suggested that re causes for this and to take preventive measures. In movable dentures may influence salivary microbial particular, systemic diseases in the elderly tend to counts, it is still unknown whether they contribute to 1 worsen the oral environment, leading to an increased an increase in the counts. The caries activity test is useful in under that examined the oral environment over time of low standing the oral environment. Information on these oral environment fac the Denture group was 7 patients after initial place tors can aid in preventing caries based on individual ment of removable prostheses with a mean age of 69 risk, and extending the life of dental restorations. The Dentate group was 6 patients who had re Narhi reported that salivary microbial counts were ceived crown and/or bridge treatment who had a greater in elderly with dentures than in those with mean age of 613 years, a mean number of remain 88 F. We se sults for unstimulated and stimulated salivary flow lected 7 oral environment factors that have a strong rate, as well as unstimulated and stimulated salivary correlation with caries risk. Unstimulated saliva was sampled with the head in a forward inclined position for 10 min in a graduated Statistical analysis tube to obtain an estimated flow rate (mL/min). Un Each result of the seven factors was compared be stimulated saliva buffer capacity was determined us tween the Dentate and Denture groups during the pe ing a laboratory saliva test (Dentobuff strip, Orion Di riod from baseline to the follow-up. Table 1 Classification of oral environment factors Risk (class) Oral environment factors 0 Unstimulated salivary flow rate (mL/min) 0. The risk factor of lated salivary flow rate and buffering capacity after stimulated salivary flow rate was unchanged in 6 of completion of the prosthetic treatment. However, the significant differences for the unstimulated salivary amount of saliva decreased in one patient. There flow rate and the unstimulated salivary buffering ca were no significant differences. The unstimulated salivary flow rate decreased in the Dentate group showed an increase in the in only one patient for each group. However, low car amount of saliva at the one year follow-up, no change ies risk was maintained in both groups for unstimu in risk was noted in the other 4 subjects. All subjects showed low risk to the buffering capacity of stimulated saliva, no risk except for one patient for the unstimulated salivary changes were noted in 6 of the 7 patients in the Den buffering capacity test. The incidence of systemic diseases in creases with age, which influences the oral environ Fig. On the other hand, no risk changes were noted in in the elderly should be followed over time. No signifi cused on patients who were wearing their first remov cant differences were noted between the two groups. No significant differences than in those with fixed prostheses, indicating that the were noted in either group. Although they that study did not make it clear when the number of had a class 0 risk at baseline, 4 of them increased to bacteria increased in the patients with removable den Vol. However, the risk in present study was designed to follow up the changes creased in two of the subjects at follow up, which may that occurred over time in patients who were wearing have been caused by a decrease in the amount of sa their first partial dentures and who initially had low car liva. No caries were noted in the Denture group in companies aging causes various problems in the oral this study after one year of follow up. It has been reported that although saliva se tected in uneven regions of teeth, such as pits, fis 15,16 creted from the submandibular and sublingual glands sures and carious lesions. It seems that removable dentures do not signifi complete dentures than that in dentate subjects. No significant differences adhere to rough surfaces, and acrylic resin denture were noted in the Dentate group either. Journal of Osaka Dental University, October 2014 dentures, clasps, or a lack of oral hygiene. Our results ferences in the oral environment of the elderly wearing fixed prostheses and those with removable prostheses. J Osaka indicate that dentures may contribute to caries be Dent Univ 2003; 37: 109114. Evaluation of a simplified diagnostic aid (Oricult-N) for de no changes were noted in the oral environment of the tection of oral candidoses. The flow rate creases in the number of lactobacilli were noted in the of whole and submandibular/sublingual gland saliva in patients Denture group one year after denture placement, receiving replacement complete dentures. Ikebe K, Matsuda K, Morii K, Furuya-Yoshinaka M, Nokubi T, as a result of changes in the number of lactobacilli. Association of masticatory performance with age, Therefore, future investigations should be done on posterior occlusal contacts, occlusal force, and salivary flow in older adults. A longitudinal study of streptococcus mutans colonization in infants after tooth eruption. Nomura Y, Takeuchi H, Kaneko N, Matin K, Iguchi R, Toyo Fixed Prosthodontics and Occlusion in Osaka Dental Univer shima Y, Kono Y, Ikemi T, Imai S, Nishizawa T, Fukushima K, sity. Feasibility of eradication of mutans streptococci Promotion of Science, Grant-in-Aid for Scientific Research from oral cavities. Stimulated salivary flow rate, pH and lactobacillus sms, and oral health in the home-dwelling old elderlyAfive and yeast concentrations in persons with different types of year longitudinal study. The main aim of this study is to assess the Candida albicans in complete denture wearers with angular chelitis. Though Candida albicans is the predominant pathogen in angular chelitis, other species may be present which are equally pathogenic.

The therapeutic market Despite the fact that cannabis has been used for various medical purposes for thousands of years (and has a safety profile that is superior to alcohol in many respects) medications kidney disease purchase generic cytotec,2 there are surprisingly few therapeutics containing cannabis that have been approved by major regulatory authorities symptoms ketosis generic cytotec 100mcg on-line, with worldwide sales totaling only around $53m in 2018 according to Evaluate Pharma medications during pregnancy buy genuine cytotec on line. However treatment whooping cough discount generic cytotec canada, Epidiolex was only launched at the end of 2018 and is expected to have $1 medications japan buy cytotec 200mcg with amex. Also the World Health Organization treatment quietus tinnitus order cytotec without a prescription, in January of 2019, called on a rescheduling of cannabis to facilitate trade for medicinal and scientific purposes. First, Hatch-Waxman exclusivity is only three years for a product that is not a new chemical entity. And any granted patents will likely be challenged once the Hatch-Waxman exclusivity expires. This challenging intellectual property landscape is likely a major reason that larger biotechnology and pharmaceutical companies have not involved themselves in this space. Besides the possibility of cleaner and broader intellectual property, these cannabinoids may also have a differentiated efficacy and toxicity profile (see Exhibit 6). Research into these minor cannabinoids is still in relatively early days due to the Cannabis | 30 April 2019 5 expense of harvesting them, but new synthetic processes promise to make them available at a lower cost, which would encourage additional research. Believed to have efficacy with regards to pain, anxiety, depression, nausea, spasms and certain cancers. Also thought to work against pain, anxiety, depression, nausea, insomnia, spasms, psychosis and certain cancers. Preliminary studies indicate a potential to treat acne, diarrhea, pain, inflammation, depression, anxiety, multiple sclerosis and increase bone growth. Potential against bacteria, epilepsy, inflammation, anorexia, cancer, insomnia, glaucoma, bone healing and pain. Potential to treat Tetrahydrocannabinolic acid inflammation, nausea, cancers and act as a neuroprotective. In one study of 31 typical and borderline Dravet patients (14 were typical Dravet, 17 were borderline) who were 3 Sakauchi et al. The mortality rate is high, although the exact percentage varies based on the study and ranges between 3% and 25%. With an average annual price for Epidiolex at $32,500, this suggests a $3bn to $4. Cannabinoids in other approved indications Marinol and Cesamet have been approved for chemotherapy-related nausea and a review of data from 23 trials indicates that cannabinoids are superior to placebo and approximately in line with other anti-emetic therapies, though the cannabinoids were associated with dizziness, dysphoria, euphoria and sedation. However, in a per-protocol analysis, which excluded 21% of patients who had protocol violations, Sativex improved spasticity scores by 1. None of the 15 other secondary endpoints were positive on an intent to treat basis but three were positive on a per protocol basis. Cannabinoids for pain After epilepsy, pain is probably the area with the highest quantity of evidence associated with the efficacy of cannabinoids and is simply an enormous market. In Europe, the prevalence of moderate to severe pain in the adult population is estimated to be similarly high at 19%12 (around 80 million people). However, while pain is a very promising and large market for cannabinoids, the clinical data have been a little inconsistent. However, usage data from states that have legalized medical cannabis indicates that patients are using it for pain and this has led to less opioid use. In one survey of 244 medical cannabis patients in Michigan, cannabis use was associated with a 64% decline in opioid use,14 a tremendous decrease that would speak to at least some efficacy for the drug. Also, in an analysis of Medicare Part D data, medical cannabis legalization was associated with a statistically significant 11. Importantly, there were no psychotropic effects and no discontinuations due to adverse events. Only data so far have been Phase I study in healthy Pharma tetrahydrocannabinol volunteers. The second study examined 24 patients in placebo and dose escalation cohorts (ranging from 2. It reached similar results, showing improvement in symptom ratings of motor tics (p=0. There is also some data related to using cannabinoids in the treatment of recurrent glioblastoma. According to the Central Brain Tumor Registry of the United States, glioblastoma represents 15% of all brain and central nervous system tumors, amounting to approximately 11,000 new cases per year. The retail market the market for legal cannabis has been growing very quickly and has a meaningful size, but it is a small fraction of its full potential. If the level of consumption per capita becomes similar in the states that recently legalized recreational cannabis to that seen in Colorado, the market could grow to $18. And these sales are likely to have a major impact on other industries, including the liquor industry. In a study of purchase data between 2006 and 2015, medical cannabis legalization by itself was associated with a 15% reduction in alcohol sales. While the illegal market was primarily focused on the buying and selling of cannabis flower product itself, the legal market has evolved into something more complex. Approximately half of product sold is still flower, but the rest is concentrate (vape, wax and shatter), edibles and pre-rolled (see Exhibit 10). Exhibit 10: Market share of cannabis product types by state, 2017 Flower Concentrates Edibles Pre-rolled Others California 55 25 12 5 4 Washington 55 23 9 11 1 Oregon 51 22 14 7 6 Colorado 48 27 15 5 5 Source: Statista Also, the markets seem to mature quickly with the high growth phase lasting two to three years and then levelling off as outlets to purchase product have already become ubiquitous (see Exhibits 11 and 12). Another factor that might be curtailing sales growth in individual states is the feedback effect from legalization becoming more widespread in more areas of the country. Around 12% of cannabis use in Colorado is estimated to have come from tourists in 2017, with California being the largest home state for these visitors. Another important item to note is that medical cannabis sales tend to fall post-recreational legalization as medical prescriptions are no longer necessary. In Colorado, medical cannabis had represented 39% of legal sales two years after legalization but currently only accounts for around 20% of sales. Exhibit 11: Colorado Legal Cannabis Sales (monthly) Exhibit 12: Oregon Legal Cannabis Sales (monthly) Source: Colorado Department of Revenue Source: Oregon Liquor Control Commission In addition, as more producers and retailers enter the growing cannabis market, prices have fallen precipitously (see Exhibits 13 and 14). In Colorado, according to the Colorado Department of Revenue, wholesale prices fell 47% from the beginning of 2017 to the beginning of 2019, while they fell by almost 40% in Oregon for indoor growers and over 50% for outdoor growers over the same period, according to the Oregon Liquor Control Commission. Recreational producers harvested 2,000 metric tons of cannabis in 2018 with current inventory levels amounting to 6. The Oregon Liquor Control Commission estimates that if all pending producer applications were approved, production would nearly double, so there is probably no end in sight to the supply glut and falling prices. However, just as we saw with the dot-com businesses, branding helps to separate the wheat from the chaff. New Frontier Data estimates that the recreational cannabis market in Canada with reach $4. Exhibit 15: Estimated size of key European cannabis markets in 2028 post-legalization Medicinal cannabis market Recreational cannabis market Total market value value 2028 (bn) value 2028 (bn) (bn) Germany 7. In July 2017, the Greens proposed the Cannabis Control Act, which would legalize recreational cannabis and create a regulated market on the supply side. Currently the Greens are polling at twice their level in the last election and may become the second-largest party in Germany. If that happens, they may be able to form a government and work to legalize cannabis in the country. For the other major countries in Europe, the chance of broad legalization is quite slim in the foreseeable future. In Italy, the Five Star Movement has called for legalization but its coalition partners are against it. Five Star has not made it much of a legislative priority, so legalization is unlikely in the near future. The next election is scheduled for 2023 but none of the other major parties or coalitions have come out for any major reform. Taxes incentivize legalization One major motivator for the recent legalizations has been to transform an illegal market into a legal one that could be taxed. There is significant pressure on countries to find new sources of revenue due to massive unfunded liabilities related to state employee pensions and retiree health benefits as well as servicing debts from prior budgets. Exhibit 16: State tax rates for recreational cannabis Year of commencement of Effective sales tax rate (total Tax revenue ($m) recreational sales local + state taxes and fees) Colorado 2014 ~29% 263. Current methods of extracting or manufacturing cannabinoids have some significant drawbacks. Plant-based extraction of cannabinoids is time consuming (three to 10 months just to cultivate the plant), which also requires a high degree of purification to remove unwanted pesticides, molds, fungi or bacteria, residual solvents and non-target cannabinoids. Also, it is not cost effective to extract the 100+ minor cannabinoids from plants, as cannabinoids that make up <1% of the plant cost over $100,000 per kilogram (see Exhibit 16) to produce. Cannabis | 30 April 2019 13 Exhibit 17: Cost curve for extracting cannabinoids Source: Cronos Group Chemical synthesis is not as time consuming as plant-based extraction but still takes weeks and has a purity problem as the process results in excessive waste and the creation of stereoisomers, which could affect the efficacy and safety of the product. Through biosynthesis, purer, more cost efficient product may be created through cell culture bioreactions. There are several key hurdles to reconstituting the biosynthesis of cannabinoids in a synthetic biologic system. The key enzymes for the production of cannabinoids and cannabinoid precursors must be introduced transgenically into the system. Also, although the molecular building blocks for cannabinoids are present in metabolic pathways outside of cannabis, sufficient quantities of these molecules must be generated to support cannabinoid synthesis at commercially significant levels. Another competitor is Librede, which holds a patent to manufacture cannabinoids in yeast (patent number 9,822,384). This is a full biosynthetic process possible because yeast is able to make higher-order enzymes and has the metabolic capability to feed enough starting materials to the cannabinoid biosynthetic pathway. However, this company has not yet scaled the process; although in 2018 it obtained a $1. Other players in this space have made big announcements related to their entry but it is unclear at what stage they are at in developing a fermentation process. In September 2018, Ginkgo Bioworks announced a deal with Cronos Group in which Cronos will pay Ginkgo up to $122m to develop a biosynthesis process for eight target cannabinoids. Of this $22m will be to fund R&D and foundry expenses with the rest of the potential payout related to hitting milestones, namely achieving a production cost of less than $1,000 per kilogram at a scale of greater than 200 liters. It is unclear whether this is achievable due to the large amount of expensive inputs and recent data from InMed, which indicated that the yield from yeast28 was a fraction of the yield from E. Ketamine has shown remarkably rapid efficacy in treatment-resistant major depression. Historically there have been few approvals for treatment-resistant depression, with the only medical therapy being Symbyax (a combination of the antipsychotic olanzapine and fluoxetine) developed by Eli Lilly and approved in 2003. Otherwise, the only other approved treatments are electroconvulsive therapy and vagus nerve stimulation. Its dissociative properties, which were of fast onset (~10 minutes) and short duration (one to two hours), caused it to gain popularity as a club drug. Interest in ketamine as a treatment for depression intensified after remarkable data from an 18-person trial using intravenous ketamine was published. It normally takes weeks for antidepressants to be able to show efficacy in patients, but ketamine was able to show statistically significant improvement over placebo just 110 minutes post-injection, with the responses remaining significant for a week. What made these data especially powerful is that these patients were very treatment resistant. This is why Johnson and Johnson instead developed the S-isomer of ketamine, esketamine, for treatment-resistant depression, this time as an intranasal formulation. It is unclear what the differences between esketamine and ketamine are in terms of efficacy, but it is thought to have milder dissociative effects, although administration is still needed in a clinical setting. Another drug with historical recreational use that has potential in treatment resistant depression is psilocybin, the active ingredient in magic mushrooms. Psilocybin has been used for healing and divination in indigenous cultures of Central and South America for years but was only discovered by westerners in the 1950s. In one trial in 12 treatment-resistant depression patients who had a mean duration of illness of 17. In another trial of 75 healthy volunteers, patients receiving the higher dose saw significant improvement in their ratings of gratitude, life meaning and 29 Kessler et al. Volume 3, Issue 5, P481-488, May 1, 2016 Cannabis | 30 April 2019 16 purpose and interpersonal closeness four months after their second and final dose. Psilocybin has also had positive data in some small open-label trials in the treatment of addiction.

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You can: Attend at the suggested date and time Ask to reschedule the meeting and suggest other dates and times you can meet Ask to participate through a telephone conference Decide that it is impossible for you to attend and tell the school that they may go ahead with the meeting and talk with you about the results afterward (If you choose this option medications made easy purchase discount cytotec, the school must send you copies of all the reports and any forms that they filled out during the meeting medicinebg generic 100mcg cytotec. This will help you remember important information you want to share and questions you want to ask symptoms 37 weeks pregnant purchase cheapest cytotec and cytotec. A group of people from the school or school district will be at the eligibility staffing medications reactions generic cytotec 200mcg online. The questions include: What special learning needs does your child have because of the disability You have the right to receive copies of evaluations and reports at no cost to you treatment urticaria buy cytotec master card. If your child is still struggling 300 medications for nclex buy discount cytotec 200 mcg on line,s thhe school will keep working with yoou to find wayss to help. If youry child is doingd betterr, the school will continuue to monitoor progress tot make sure that your childc continuues to be successful. The notice will tell you the day, time, and place suggested for the meeting; who will be there; and why the meeting is being held. If the school is going to invite someone from any agency other than the school district, you must give your permission. If you are going to invite someone, it would be helpful if you let the school know who you are inviting. You will be asked to sign a different form to give your permission for services to begin for your child. Present Levels of Academic Achievement and Functional Performance the present level statement describes what your child is able to do and what they struggle with in academic subjects and functional skills. It may also include information about how your child behaves or communicates with others. Measurable Annual Goals Measurable annual goals state what your child needs to learn in order to progress in the general curriculum and to meet other needs related to their disability. Here are some examples of annual goals: By the end of the year, John will independently read a fourthgrade textbook and answer comprehension questions with 80 percent accuracy. Benchmarks are major milestones between the present levels of performance and annual goals. The benchmarks and shortterm objectives should not be so small that your child could achieve them in a day or two. It may also list the title of the person who will make sure that your child receives each service. Services, aids, and supports are help that your child may need in order to benefit from school. They are devices and services that allow children with disabilities to be educated with children without disabilities as much as possible. Some children do not need any additional services, aids, or supports, while other children need several. Accommodations Your child may need changes in teaching or testing in order to make progress and demonstrate what they have learned. Accommodations are changes to the way a student accesses instructions and demonstrates what they know. Students who need accommodations but not modifications usually work toward a standard diploma. They may include changes to content, requirements, and expected levels of mastery. Modifications may include partially completing a course or program requirement or getting instruction in the access points for students with significant cognitive disabilities. Students who need modifications may not be able to earn a standard high school diploma. An accommodation to a state or districtwide assessment should only be requested when used regularly in the classroom setting. If your child is using an accommodation in the classroom that is not allowed for state assessments, you must sign forms that describe the accommodation and tell you which test(s) will not allow its use. Here are some examples of testing accommodations: An interpreter uses sign language to give the directions for a test to a child who cannot hear. Florida Alternnate Assessmment Federal and statee laws requirre that all students be inncluded in sttatewide tessting. A small nnumber of sstudents with significantt cogniitive disabilitties take thee Florida Alteernate Assesssment. Before thaat time, statees had differrent laws annd not all childrren with disaabilities could attend puublic schoolss. Ranging from least restrictive (1) to most restrictive (6), possible placements include the following: 1. General education class for all subjects, with special instruction, materials, technology, services, accommodations, or curriculum modifications 2. Instruction at home or in a hospital these different types of placements make up the range of placements. Some types of services may be available in many schools throughout the school district. In almost every case, the local public school district will be able to offer the services and placement your child needs. The book, Transition Planning for Students with Disabilities: A Guide for Families, provides important information about transitioning. Talk with the teachers about the good things you saw as well as any concerns you have. Many school districts have procedures in place to assist families in resolving disputes. Servvices that are checkked off on thhe matrix muust be servicces your child is actuallyy receiving. If you cannot go at the time suggested in the written notice, you may call the school and ask for a different day, time, or place. Read over the progress reports you received during the year and any other records you have. Here are some reasons you might ask for a review meeting before the end of the 12 months: Your child is not making as much progress as expected. If you cannot settle youry disagreeement with the school, you may ask for mediattion or forr a due process hearing. The school must have your written permission before doing any individual evaluation or testing. If you disagree with the decision, read Chapter 8 for more information about your procedural safeguards. The federal law called the Individuals with Disabilities Education Act says that as the parent of a child with a disability, you have certain procedural safeguards. Procedural safeguards give parents and schools a set of rules to help them work together. The procedural safeguards also give parents and schools ways to solve problems and settle disagreements. If you have good reason to believe that your child is not receiving a free appropriate public education, you may want to make use of your rights, including your right to mediation, to file a state complaint, and to request a due process hearing. In Florida, this transfer of rights happens when the student turns 18, unless the student has been declared incompetent under state law or has a guardian advocate who has been appointed to make educational decisions. If you do not understand the notice, call the school or appropriate contact right away. If you do not agree with what the notice says, there are steps you can take: First, contact the person named in the notice. The school must ask you to participate whenever they hold a meeting related to the identification, evaluation, or placement of your child or to the provision of a free appropriate public education to your child. No matter who asked for the meeting, when you participate, you make it easier for the school to serve your child. Be sure to let the school know before the meeting if you need a translator or an interpreter. Read over your records and the parts of this book that are about the type of meeting you will be attending. Make notes about things you want to say or the questions you want to ask and take them to the meeting. It is helpful to let the school know when you are bringing someone with you to the meeting. The Right to Give, Not Give, or Withdraw Consent For some actions, the school only has to let you know what they have decided to do or not do (give you notice). You will be asked to sign a form that says you agree to what the school is planning. If the school staff refuses to make the change, they will let you know in writing. The school staff may try to help your child in another way, or they may suggest mediation or ask for a due process hearing. Most of the time you and the school staff will be able to work together and agree on what will be done for your child. Remember, for some actions, the school must give you a written notice but does not need your consent. Steps in Solving Problems From time to time, you and the school staff may disagree about what is fair or needed for your child. Some disagreements can be solved easily, while others may take more time and effort. The first step in solving a problem is to make sure that everyone understands the problem. Taking a complaint to someone who cannot make decisions is not a good use of time for you or your child. Dispute Resolution If you and the school district are still not able to agree about what is needed for your child, you may decide to ask for mediation, file a state complaint, or ask for a due process hearing. Mediation, formal complaints, and due process hearings all have the same purpose: to solve problems. They are designed to make sure that children with disabilities receive a free appropriate public education. More information about the dispute resolution methods below and the forms you need to complete if you want to use one of them can be found online at. During a mediation session, a trained and impartial mediator will help you and the school district resolve your disagreement about the identification, evaluation, placement, or free appropriate public education of your child. The purpose of mediation is not for one side to win, but for both sides to come to an agreement. The mediation session will give you and the school district a chance to: Talk about the problem Explain your points of view Come to an agreement that is best for your child the mediator will not decide how to solve the problem.