The use of nanoparticles, in many different fields, is rapidly increasing. What substances, and to what extent they exist in food and supplements, and the prevalence of such products on the market, is of interest to the Swedish National Food Agency. Answering those questions, as well as providing information regarding their potential toxicity, was the intent of this thesis. To understand the difficulties, and possibilities, in analyzing nanoparticles in food, a methods-section was included, covering the most common techniques, the theory behind them and when they may be used. It became abundantly clear that analyzing nanoparticles in food, and investigating their potential toxicity, is anything but simple, and requires a combination of many techniques. Quite surprisingly, it seems the occurrence of nanoparticles in food, as today, are not added on purpose, since not one nanosubstance to be used in food has been approved by EU. Rather, studies have revealed they originate from a nanosized fraction of food additives, such as TiO2 (E171), which has attracted particular attention in this report. This nanofraction may be as large as 40%, and the estimated total intake of TiO2 (as stated by EFSA) is 1.28 mg/kg/person, resulting in quite an amount of nano TiO2, provided the numbers are correct. The toxicity of silver has also been reviewed, since the colloidal form, which includes nanoparticles, is quite common as a health supplement. Toxicity studies are not unambiguous though, some indicate geno-and–cytotoxicity and others do not. Importantly, the toxicity studies on TiO2 have not been done on E171, but on many other forms of TiO2, whose relevance is difficult to predict. TiO2 is, however, classified as a possible carcinogen by IARC. Several groups have taken an interest in a potential relation between particle intake and various chronic inflammatory diseases, also discussed in this report. In conclusion, the size, modifications of E171 and its toxicity, requires more attention in order for food authorities to confidently ascertain healthy food for the public.

Isotretinoin är ett licensläkemedel som främst används för att behandla svår akne hos patienter som inte har blivit hjälpta av andra behandlingar och akne med risk för ärrbildning. Att akne är en mycket vanlig hudsjukdom visade man bland annat i en svensk undersökning där en av tre ungdomar har besvär som kräver behandling. Ca 85% av alla tonåringar har akne. Isotretinoin är det effektivaste medlet mot akne idag. Konventionell behandling med isotretinoin i doser mellan 0,5-1,0 mg/kg .dag är effektiv men ger ibland svåra biverkningar. De dos-relaterade biverkningarna är anledningen till att många inte klarar av att fullfölja behandlingen. Syftet med detta litteraturarbete var att undersöka om alternativ behandling med låg-dos isotretinoin (0,20-0,4 mg/kg.dag) kan minska biverkningarna men ändå ge lika bra resultat som den konventionella behandlingen samt att undersöka om läkemedlet är lämpligt att användas även vid mild och måttlig akne så att många fler kan få hjälp att bli fria från sina besvär. Via Linnéuniversitetets bibliotek gjordes en sökning i databaserna Pubmed och Meshdatabase för att hitta relevanta artiklar för detta arbete. Enligt de studier, som har granskats i detta litteraturarbete, är låg-dos behandling med isotretinoin ett bra och möjligt alternativ för patienter med mild till måttlig akne och ger färre och mildare biverkningar i jämförelse med konventionell behandling. Även svår akne kan med fördel behandlas med lägre doser isotretinoin, vilket är ett bra alternativ till patienter som inte klarar av konventionell behandling. Det krävs dock fler studier som kan bekräfta redan tillgängliga studier och deras resultat.

Bakgrund: Övervikt och fetma har ökat i världen de senaste åren. För att behandla dessa tillstånd finns idag endast ett godkänt läkemedel och det är orlistat. Liraglutid, som är en långverkande GLP-1 analog, kanske kan vara ett alternativ till orlistat. Idag är Liraglutid ett läkemedel som används som tilläggsterapi vid behandling av diabetes mellitus typ 2 (DM2). Flera studier visar att Liraglutid har en viktminskande effekt som troligtvis beror på en kombination av effekter. Dessa effekter involverar troligen aptitregleringen som styrs av hypotalamus och effekter på magtarmkanalen.    Syfte: Syftet med detta arbete är att undersöka vilken viktminskningseffekt liraglutid har när det används som monoterapi hos patienter med eller utan DM2.                                                                                                            Metod: Detta arbete är en litteraturstudie. Sökning efter randomiserade kliniska studier skedde på PubMed. 6 studier inkluderades i arbetet.                                                                                                                                 Resultat: Patienterna som gick ner mest i vikt fick liraglutid dosen 3,0 mg. Dessa patienter var individer med fetma utan DM2 och gick i medel ner 7,2 kg efter 20 veckor samt 7,8 kg efter 1 år. Patienter som behandlades med liraglutid i doser från 1,2 mg till 2,4 mg gick ner mellan 2,1 kg (1,2 mg i 52 veckor) och 6,3 kg (2,4 mg i 20 veckor). Bland patienterna med diabetes mellitus typ 2 gick gruppen behandlad med 1,9 mg liraglutid ner mest i vikt (-2,99 kg). Lägre doser från 0,045 mg till 0,75 mg gav inte lika stora resultat på viktminskning. Slutsats: Liraglutids viktminskningseffekt är dosberoende. Patienterna som gick ner mest i vikt fick högsta dosen och också instruktioner om att hålla en kalorisnål diet. Grupperna som fick de lägsta doserna av liraglutid tappade inget eller väldigt lite i vikt. Både patienter med och utan DM2 gick ner i vikt. I behandlingen utav DM2 kan viktminskningseffekten vara till värde på grund av kopplingen till övervikt och fetma. För att rekommendera liraglutid som ett läkemedel för behandling av övervikt och fetma kan det troligtvis krävas fler studier där viktminskning är ett primärt effektmått och fler studier som undersöker säkerheten av läkemedlet i högre doser hos patienter både med och utan DM2.

Över hela världen anses huvudlusen (Pediculus humanus capitis) vara den vanligaste ektoparasiten hos människa. I Sverige säljs det ca 100 000 förpackningar med avlusningsmedel varje år, så problemet är uppenbart. Resistensutveckling hos huvudlöss tros vara en viktig orsak till ökningen av dessa parasiter. I maj 2010 kom Läkemedelsverket ut med nya behandlingsrekommendationer där medicintekniska produkter är förstahandsval. Malation respektive permetrin ligger på en tredje respektive fjärdeplats i denna rekommendation. Ivermektin är ett annat medel som har använts bland annat mot skabb men även som massbehandlingar i områden med låg socioekonomisk status. Syftet med denna studie var att undersöka effekten av dimetikon, malation, permetrin och ivermektin som behandling mot huvudlöss. Effekten av behandling av huvudlöss varierar mellan olika preparat. Andelen lusfria efter 1-2 behandlingar med dimetikon varierade mellan 60-97 %. För malation och permetrin varierade behandlingsutfallet mellan 33-85% respektive 12-67 %. Ivermektin visade sig vara mest effektiv (95 %) då det gavs som en oral dos på 400 µg/kg kroppsvikt. Effekten i samtliga studier mättes genom att bedöma hur många individer som var lusfria efter behandlingen.  Slutsatsen i detta arbete är att inget av de behandlingsalternativ som lyfts fram visar på hundraprocentig effektivitet. Den varierade effekten av malation och permetrin orsakas sannolikt av en ojämnt geografisk utbredd resistensutveckling runt om i världen. Dimetikon är ett bra alternativ då risken för resistensutveckling anses som låg och den har en god effekt mot huvudlöss.  Ivermektin kan vara ett alternativ vid svårbehandlade fall av huvudlöss men bör användas med försiktighet då redan resistensutveckling har påträffats hos skabb.

<p> The pediatric mental health burden in the United States (US) is substantial, with more than 4 million children meeting diagnostic criteria for a mental health disorder. As of 2014, this number represented 20% of US children and adolescents. In 2010, mental health disorders are estimated to cost children and their families $247 billion dollars annually and severely impact quality of life for children and their families. From 2007 to 2010, inpatient admissions for mental health disorders in pediatric patients increased 24% and mood disorder admissions in pediatric patients increased 80% from 1997&ndash;2010. An estimated $11.6 billion was spent on pediatric mental health hospitalizations from 2006 through 2011, with public sources such as Medicaid and Medicare responsible for approximately 50% of the payments, leaving 50% to private payers. This economic and clinical concern has led pediatric medical associations and health quality agencies to increase support and funding for pediatric mental health research and treatment. </p><p> Medication therapy is a common intervention in mental health treatment and atypical antipsychotics are increasing in utilization, often becoming first-line therapy. Despite available data describing the need to treat pediatric mental health conditions, the available evidence for clinical effectiveness and economic impact of atypical antipsychotics (AAPs) has many shortfalls. Most available research is derived from patients utilizing publicly-funded medical care, such as Medicaid or Medicare resources, with little data available about patients with privately-funded care. To help address this gap in the literature, we used a large, privately-insured, US population for our analysis. We examined if the increased trend in AAP utilization from previous research is also present in this pediatric population. Considering the payer perspective, we evaluated the cost of AAP medication therapy based on most recent utilization. </p><p> Available studies lack information about the direct costs of pediatric mental health treatment and efficacy of psychiatric medications in the pediatric population. Most efficacy studies are based on clinical trials necessary for pediatric indication approval from regulatory agencies such as the Food and Drug Administration (FDA). Many of the AAP medications do not have pediatric clinical trial evidence available and are frequently utilized without pediatric indications. The available data suggests that off-label prescribing is not an uncommon practice in the pediatric patient population. </p><p> Approximately half of atypical antipsychotics do not have pediatric indications but are increasingly used, particularly in treating behavior disorders, due to such factors as improved patient compliance and improved side effect profiles. Limited formal studies examining atypical antipsychotic use compared to other agents in the class have been conducted. Studies with direct comparisons have yet to be conducted in the pediatric population with mental health disorders. </p><p> The manuscripts that comprise this dissertation aim to provide new insights into available trend and utilization patterns of atypical antipsychotic medication use in children. This research characterized the prevalence of atypical antipsychotic use in pediatric patient with mental health conditions in a large, privately insured US population, evaluating the diagnoses associated with treatment and estimate the cost of AAP medication therapy in this population. This research determined if the trends observed in publicly-insured children persist in the privately-insured, pediatric patient. The analysis evaluated annual trends in prevalent use of atypical antipsychotic medication over 6-year period in this pediatric population and evaluated the appropriate use of AAPs for mental health diagnoses. Lastly, an evaluation determined if specific antipsychotic therapy delayed time to readmission among privately-insured children following a psychiatric hospital admission. The results of this dissertation will provide new insights regarding the trends and direct medication costs of atypical antipsychotic agents when utilized in pediatric patients with mental health disorders. </p><p> <u>Manuscript 1:</u> This analysis focused on characterizing the most recent (2015) AAP use in the pediatric population, using a large, US population of privately- insured children. The study evaluated if the prevalence data observed among publicly insured children persists. Characterization of the prescribing trends for atypical antipsychotics and the medication costs of the use in this population were examined. Patterns of use across demographics and associated mental health diagnoses were characterized by the class of medication. This study focused on the prevalent use of AAPs in pediatric patients, evaluated the mental health diagnoses associated with AAPs and the direct cost burden of medication therapy associated with this use of AAP in the pediatric population to the private payer. </p><p> <u>Manuscript 2:</u> This research evaluated the trends in the prescribing of atypical antipsychotic medications from 2010 through 2015 in this privately-insured pediatric population. The trends of AAP use in the pediatric population over six years were examined. The associated mental health diagnoses corresponding with AAP prescribing were described to examine the off-label diagnoses treatment prevalence in this population. (Abstract shortened by ProQuest.) </p><p>

The primary objective of the research was to investigate the pharmacodynamics of digoxin in dogs. Initially an assay specific for digoxin in the presence of its major metabolites, viz., digoxigenin, digoxigenin mono-digitoxoside, digoxigenin bis-digitoxoside and dihydrodigoxin was developed using HPLC-RIA. Methodology for non-invasive measurement of left ventricular ejection time (LVET) and other systolic time intervals (STI) in beagle dogs were developed. This involved surgery for exteriorization of the carotid artery in the dogs and subsequent measurements of LVET and STI after recovery. STI, heart rate (HR) and digoxin levels were monitored in normal beagle dogs administered 0.05 mg/kg or 0.025 mg/kg i.v., infused uniformly over a 5 min. period. The STI did not lend itself to pharmacodynamic modelling. The LVET, QS2 and P-R interval were found to be inversely, but linearly, related to the heart rate. Therefore, the bradycardic response to digoxin was extensively investigated in beagle dogs. Pharmacodynamic models evaluated for modelling the bradycardic response to digoxin were: the pharmacokinetic model with a direct linear link, the linear model, the physiologic-pharmacokinetic model with direct linear link and the effect compartment model. The physiologic pharmacokinetic model was simulated using SPICE2 which uses network thermodynamics to simulate biological systems. Criteria for the selection of appropriate models were established. Using the established criteria, the effect compartment model was demonstrated to be the best model. The implications and applications of pharmacodynamic models in general and specifically of the pharmacodynamic model for the bradycardic response to the digoxin are discussed.

During the past few decades, analogs of purine nucleosides have been described that are modified either in the heterocyclic base, sugar moiety or both, and many of these modified nucleosides display antiviral and/or antineoplastic activity. The Class II mesoionic purinones are isosteric with their non~mesoionic purinone counterparts. It is conceivable that the mesoionic purinone nucleosides might constitute an entirely novel class of modified nucleosides with potential chemotherapeutic activity. That the mesoionic heterobases are bioisosteric as well as isosteric with non-mesoionic purinones was realized by demonstrating that certain mesoionic xanthine derivatives, such as Anhydro-8-ethylw-5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide and Anhydro-6-p-chlorobenzyl-8-ethyl-5-hydroxy-7-oxo—l,3,4—thiadiazolo [3,2-a]pyrimidinium hydroxide were comparable in potency to test compound, theophylline as inhibitors of adenosine binding at the A1 site. Three different types of mesoionic nucleosides were subsequently designed and synthesized as potential antineoplastic agents. Mesoionic thiadiazolopyrimidine nucleosides, i.e. Anhydro-6-ethyl-8-(2’,3',5'-tri-O-acetyl-D-ribofuranosyl)MS-hydroxy-7-oxo-l,3,4~thiadiazolo{3,2-a]pyrimidinium hydroxide and Anhydro-8-(2',3'.5’-tri-O-acetyl-D-ribofuranosyl) -5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide were designed to serve as potential pro-drugs of 2-amino-l,3,4~thiadiazole mononucleotide which has been reported to be a potent inhibitor of inosine monophosphate dehydrogenase. The O~acylated derivatives of the target compounds were prepared by the acid catalyzed condensation of D-ribose with 2-ATD followed by protection of the hydroxyl groups and subsequent cyclization to the mesoionic products; anomeric separation was achieved by column chromatography; All attempts to deprotect the hydroxyl groups of the mesoionic nucleosides resulted in hydrolytic ring-opening of the mesoionic heterobase. The 0-acetyl derivatives of the mesoionic thiadiazolopyrimidine nucleosides were evaluated for antineoplastic activity but were found to be inactive. The mesoionic thia-zolinopyrimidine nucleoside, i.e. Anhydro-6-ethyl-8-(D-2‘-deoxyribo-furanosyl-5-hydroxy-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidinium hydrox- ide, prepared in a similar fashion to the mesoionic thiadiazolopyrimie- dine nucleosides, was designed as a potential inhibitor of the enzyme thymidylate synthetase. The mesoionic thiazolinopyrimidine nucleoside, was obtained as the a anomer and was not evaluated for antineoplastic activity. The mesoionic imidazothiazine nucleoside, i.e. Anhydro-l- (2',3',5'-tri-O-acetyl-D-ribofuranosyl)-5-hydroxy-7-oxoimidazo[2,l-b] thiazinium hydroxide was prepared as a potentially useful agent, due to its structural and isosteric similarity with purine nucleosides. The mesoionic imidazothiazine nucleoside was prepared by a cyclization reaction between the tri-0-acetyl-D-ribofuranosyl imidazole-2-thione and carbon suboxide. The mesoionic imidazothiazine nucleoside was not stable at room temperature or in aqueous Solution. While the results of this study on the chemotherapeutic utility of mesoionic nucleosides was rather discouraging, knowledge has been.gained that might be of value for the future design and synthesis of useful mesoionic nucleosides.

<p> Exemestane (EXE) is an endocrine therapy used to combat postmenopausal breast cancer. Several studies have reported substantial differences in clinical outcomes between EXE-treated patients, as well as inexplicable variability in serum concentrations of EXE and its major metabolite, 17&beta;-dihydroexemestane (17&beta;-DHE). For many pharmaceuticals, drug response is influenced by patient-specific genetic factors related to xenobiotic metabolism. Thus, it is possible that allelic variation in genes involved in EXE metabolism contributes to inter-individual differences in patient outcomes, possibly through differential EXE clearance or varied rates of metabolite formation. Historically, knowledge of phase I EXE metabolism has been extremely limited with significant ambiguity surrounding the identity of the specific hepatic enzymes involved. To address this gap in knowledge, <i>in vitro</i> studies were undertaken to better characterize hepatic phase I EXE metabolism and in particular, to assess the impact of genetic variation in drug-metabolizing enzymes on the production of EXE metabolites with inhibitory activity against aromatase. </p><p> The first part of this dissertation describes the identification of phase I EXE metabolites and details their capacity to suppress estrogen synthesis. Four metabolites, including 17&beta;-DHE, were detected in incubations of EXE with pooled human liver microsomes. 17&beta;-DHE and a novel metabolite, 17&alpha;-DHE, were formed in incubations of EXE with pooled human liver cytosol. The identities of phase I EXE metabolites were confirmed through comparison to reference compounds using UPLC/MS/MS. Anti-aromatase activity assays (AAA) revealed that 17&beta;-DHE is the only phase I EXE metabolite formed by human liver fractions that appreciably impedes estrogen formation. AAA also suggest that the inhibitory potency of EXE is unaffected by common nonsynonymous polymorphisms in aromatase. The latter half of this dissertation identifies hepatic enzymes that are likely to participate in phase I EXE metabolism. <i>In vitro </i> assays show that CBR1, AKR1Cs, and multiple hepatic CYP450s predominantly reduce EXE to 17&beta;-DHE with minor formation of additional inactive metabolites. Kinetic assays comparing 17&beta;-DHE formation by each wildtype enzyme to its common variant allozymes show that specific genotypes are associated with altered EXE metabolism <i>in vitro</i>. However, additional investigations are needed to determine the prognostic value of these associations for predicting <i> in vivo</i> EXE response.</p><p>

Introduction: Awareness and usage of Electronic cigarettes (e-cigs) among smokers have increased rapidly over the past few years, majorly in quitting smoking. The main objectives for this study were: 1) To estimate the prevalence and study sociodemographic predictors for e-cigs use among individuals with Chronic Obstructive Pulmonary Disease (COPD) 2) To examine the predictors and estimate the total healthcare costs among current smokers with COPD 3) To estimate the economic impact of adopting e-cigs as a smoking cessation tool among current smokers with COPD. Methods: The National Health Interview Survey data from the year 2014 was utilized to estimate the prevalence and identify sociodemographic predictors associated with e-cigs use among COPD adult population. Total healthcare costs and sociodemographic and clinical predictors among current smokers with COPD were estimated using the Medical Expenditure Panel Survey data from the year 2012-2013. Economic impact for adoption of e-cigs was obtained by developing an epidemiological cohort-Markov model from a societal perspective over the period of 5-year. The targeted population was current smokers with COPD and willing to quit smoking. Smoking abstinence for e-cigs was compared with Varenicline, Bupropion, and Nicotine Replacement therapy. Outcomes evaluated were the 1-year and accumulated 5-year total healthcare costs savings associated with e-cigs over other options. Results: Among individuals with COPD, 8.65% and 24.37% were current and ever e-cig users respectively. Current e-cigs use was found to be associated with individuals who have tried quitting smoking in the past (OR: 2.0; 95%CI: 1.05, 3.97). Adjusted total healthcare costs per patient per year among current smokers with COPD were found to be higher by $1,811 in comparison to non-smokers with COPD. The adoption of e-cigs among COPD current smokers can have a positive impact on the healthcare budget and can lead to healthcare cost savings of $37.71 million over the period of 5-year. Furthermore, a positive impact on budget were found among women and individuals with age 65 & above. Conclusion: E-cigs may be beneficial to the current US healthcare system if adopted as a smoking cessation tool among COPD individuals. However, uncertainty associated with product safety, efficacy and adherence for cessation warrants further studies and evaluation.

<p> Pancreatic cancer is the one of the leading causes of cancer-related deaths in the United States and is characterized with low survival rate and high drug resistance. Because of the redundant and highly mutated signaling pathways in pancreatic cancer, numerous combinational therapies have been sought. Currently the selection of drug combinations is largely empirical and methods of evaluating and optimizing drug combinations have not been standardized. An important reason for this is the lack of comprehensive characterization of drug mechanisms of action and causes for drug resistance. </p><p> The purposes of this dissertation are: first, to set up a paradigm for evaluating drug combinations mathematically and translating the evaluation methods from <i>in vitro</i> to <i>in vivo</i> preclinical systems; second, to serve as an example for characterizing the biological signaling pathways and drug pharmacology comprehensively with systems modeling approaches, supported with &ldquo;big data&rdquo; from advanced techniques such as proteomic analysis; and third, using such systems models, further selecting and optimizing drug combinations to reverse drug resistance and enhance efficacy. </p><p> The two drugs selected are gemcitabine, a major component in the therapies for pancreatic cancer treatment, and birinapant, an antagonist of inhibitor of apoptosis proteins (IAP). In Chapter 1, the efficacy of this drug combination was evaluated in PANC-1 cells. A basic pharmacodynamic (PD) model was developed to characterize the temporal changes in the numbers of attached and floating cells after treatments, and synergistic effects were observed for both proliferation inhibition and death induction. Measurements of cell cycle distributions and apoptosis were then obtained and a mechanism-based PD model was developed to reveal more details and capture the major features of the beneficial interactions. From the mechanism-based PD model, different exposure schedules were tested and an optimal one to achieve maximal efficacy was proposed. </p><p> Assumptions were made in developing the mechanism-based PD model in Chapter 1. In Chapter 2, a proteomic approach was utilized for a comprehensive, unbiased study of proteins perturbed by gemcitabine and birinapant to test previous hypotheses. The mechanisms of action for both drugs were characterized more intensively, and additional details were incorporated into the interaction knowledge described previously. Based on the proteomics data, reasons for gemcitabine resistance were discussed, and regulators of DNA damage responses involving DNA repair, anti-apoptosis, and pro-migration and invasion proteins were proposed as promising candidates for therapeutic targeting. </p><p> With the rich quantitative proteomics data, a network modeling approach was attempted in Chapter 3. Quantitative relationships were developed for selected signaling pathways of cell cycle regulation, DNA damage responses, DNA repair, apoptosis, NF-&kappa;B, and MAPK-p38, which were then linked to describe the cell cycle progression and apoptosis, and finally to changes in cell numbers. Based on the developed network model, simulations were made under different conditions and compared with observations, serving as a validation process. The impact of p53 mutation and p53 silencing on the efficacy of gemcitabine was tested with this model. Sobol Sensitivity Analysis was applied to select promising targets to be combined with gemcitabine. In addition, the efficacy of curcumin combined with gemcitabine was evaluated based on the model simulation. </p><p> With extensive evaluation and comprehensive characterization of the mechanisms of this drug combination in cell culture, efforts were continued to investigate the effects of the combination in a mice xenograft model. In Chapter 4, pharmacokinetic information for gemcitabine and birinapant was gathered from the literature and full physiologically-based pharmacokinetic models (PBPK) were developed to characterize drug distribution in the body and into the pancreatic tumor. The tumor concentrations then were used to drive inhibition in tumor growth and a semi-mechanistic PBPK/PD model was developed to evaluate the efficacy of the drug combination <i>in vivo.</i> Their joint effects were revealed as merely additive. The network model developed in Chapter 3 was introduced to bridge the PBPK and PD models, and reasons for the discrepancies <i> in vitro</i> and <i>in vivo</i> were explored. Model predictions showed that simultaneous dosing was preferable to sequential dosing <i> in vivo</i> with stronger suppression of the DNA repair signaling. </p><p> In summary, this dissertation proposed a paradigm for evaluating drug combinations quantitatively in preclinical systems of cell lines and xenograft models. Comprehensive characterization of drug mechanisms of action and biological systems through network modeling can facilitate the selection and optimization of candidates for anti-cancer combination therapy. The bridging of knowledge in different scales with mathematical models in different complexity helps to minimize the gap of translating from <i>in vitro</i> to <i> in vivo</i> or even from preclinical to clinical research.</p><p>