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Saptadip Samanta,1 Debasis Bagchi,2,3 Mark S Gold,4 Rajendra D Badgaiyan,5 Debmalya Barh,6 Kenneth Blum7– 12 1Department of Physiology, Midnapore College, Midnapore, West Bengal, 721101, India; 2Department of Biology, College of Arts and Sciences, Adelphi University, Garden City, NY, USA and Department of Psychology, Gordon F. Derner School of Psychology, Adelphi University, Garden City, NY, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, Southern University, Houston, TX, 77004, USA; 4Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; 5Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 6Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur 721172, West Bengal, India; 7Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University Health Sciences, Pomona, CA, 91766, USA; 8Institute of Psychology, Eotvos Loránd University, Budapest, 1053, Hungary; 9Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH, 45435, USA; 10Department of Psychiatry, University of Vermont, Burlington, VT, 05405, USA; 11Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, 78701, USA; 12Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, IsraelCorrespondence: Saptadip Samanta; Debasis Bagchi, Email saptadip174@gmail.com; saptadip.samanta@midnaporecollege.ac.in; dbagchi@adelphi.eduAbstract: The human brain not only controls the various physiological functions but is also the prime regulator of circadian rhythms, rewards, and behaviors. Environmental factors, professional stress, and social disintegration are regarded as the initial causative factors of addiction behavior. Shift work, artificial light exposure at night, and chronic and acute jet lag influence circadian rhythm dysfunction. The result is impaired neurotransmitter release, dysfunction of neural circuits, endocrine disturbance, and metabolic disorder, leading to advancement in substance use disorder. There is a bidirectional relationship between chronodisruption and addiction behavior. Circadian rhythm dysfunction, neuroadaptation in the reward circuits, and alteration in clock gene expression in the mesolimbic areas influence substance use disorder (SUD), and chronotherapy has potential benefits in the treatment strategies. This review explores the relationship among the circadian rhythm dysfunction, reward circuit, and SUD. The impact of chronotherapy on SUD has also been discussed.Keywords: SCN, circadian rhythm dysfunction, melatonin, cortisol, drug addiction

Shannon Rae Klein,1 Kenneth Blum,2 Mark S Gold,3 Panayotis K Thanos1,4 1Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; 2Center for Sports, Exercise, & Mental Health, Western University Health Sciences, Pomona, CA, 91766, USA; 3Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63130, USA; 4Department of Psychology, University at Buffalo, Buffalo, NY, 14203, USACorrespondence: Panayotis K Thanos, Tel +1 716 881-7520, Email thanos@buffalo.eduAbstract: Methylphenidate (MP) is a psychostimulant commonly prescribed for individuals with attention deficit hyperactivity disorder (ADHD) but it is also taken with and without a prescription for performance enhancement. Prior research has characterized the effects of MP on behavior, cognition, and neurochemistry. This exploratory review covers the uses of MP and examined the effects of MP on gene expression in the brain following exposure. Overall, MP causes a wide-spread potentiation of genes, in a region-specific manner; consequently, inducing neuronal alterations, such as synaptic plasticity and transmission, resulting in observed behaviors and affects. Monoamine neurotransmitters and post-synaptic density protein genes generally had a potentiating effect in gene expression after exposure to MP.Keywords: addiction, substance abuse, methylphenidate, gene expression, monoamine neurotransmitters postsynaptic density proteins, reward deficiency syndrome

Kenneth Blum,1– 7 Igor Elman,8 Abdalla Bowirrat,1 David Baron,1 Panayotis K Thanos,9 Colin Hanna,9 Rajendra D Badgaiyan,10 Mark S Gold11 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel; 2Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Institute of Psychology, Eötvös Loránd University, Budapest, Hungary; 4Department of Psychiatry, Boonshoft School of Medicine, Wright University, Dayton, OH, USA; 5Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; 6Sunder Foundation, Palm Springs, CA, USA; 7PEAKLOGIC, LLC., Del Mar, CA, USA; 8Department of Psychiatry, Harvard College of Medicine, Cambridge, MA, USA; 9Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; 10Department of Psychiatry, Case Western Reserve University and MetroHealth System, Cleveland, OH, USA; 11Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USACorrespondence: Kenneth Blum, Tel +1 404 234 5433, Email drd2gene@gmail.com

Abdalla Bowirrat,1 Igor Elman,2 Catherine A Dennen,3 Marjorie C Gondré-Lewis,4 Jean Lud Cadet,5 Jag Khalsa,6 David Baron,7 Diwanshu Soni,8 Mark S Gold,9 Thomas J McLaughlin,10 Debasis Bagchi,11 Eric R Braverman,12 Mauro Ceccanti,13 Panayotis K Thanos,14,15 Edward Justin Modestino,16 Keerthy Sunder,17,18 Nicole Jafari,19,20 Foojan Zeine,21,22 Rajendra D Badgaiyan,23 Debmalya Barh,24,25 Milan Makale,26 Kevin T Murphy,27 Kenneth Blum1,7,10,12,18,20,24,28,29 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel; 2Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, 02139, USA; 3Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA; 4Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, 20059, USA; 5Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, 20892, USA; 6Department of Microbiology, Immunology and Tropical Medicine, George Washington University, School of Medicine, Washington, DC, USA; 7Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, 91766, USA; 8Western University Health Sciences School of Medicine, Pomona, CA, USA; 9Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA; 10Division of Reward Deficiency Clinics, TranspliceGen Therapeutics, Inc, Austin, TX, USA; 11Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA; 12Division of Clinical Neurology, The Kenneth Blum Institute of Neurogenetics & Behavior, LLC, Austin, TX, USA; 13Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, 00185, Italy; 14Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, 14203, USA; 15Department of Psychology, State University of New York at Buffalo, Buffalo, NY, 14203, USA; 16Department of Psychology, Curry College, Milton, MA, USA; 17Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA; 18Department of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA; 19Department of Human Development, California State University at Long Beach, Long Beach, CA, USA; 20Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA, USA; 21Awareness Integration Institute, San Clemente, CA, USA; 22Department of Health Science, California State University at Long Beach, Long Beach, CA, USA; 23Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA; 24Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, WB, 721172, India; 25Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil; 26Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA, 92093-0819, USA; 27Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA; 28Department of Psychiatry, University of Vermont School of Medicine, Burlington, VA, USA; 29Institute of Psychology, ELTE Eötvös Loránd University, Budapest, HungaryCorrespondence: Igor Elman; Kenneth Blum, Email dr.igorelman@gmail.com; drd2gene@gmail.comAbstract: Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.Keywords: addiction, affective, alcohol, anti-reward, anxiety, depression, dopamine, cancer, genes, cardiovascular, cognitive, medical, motivation, social isolation, reward deficiency

Kenneth Blum,1– 5 Panayotis K Thanos,6 Colin Hanna,6 Mark S Gold,7 David Baron,2 Igor Elman8 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel; 2Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Institute of Psychology, Eötvös Loránd University Budapest, Budapest, Hungary; 4Department of Psychiatry, Boonshoft School of Medicine, Wright University, Dayton, OH, USA; 5Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; 6Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; 7Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; 8Department of Psychiatry, Harvard University College of Medicine, Cambridge, MA, USACorrespondence: Kenneth Blum, Email drd2gene@gmail.comAbstract: Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.Keywords: GWAS, candidate genes, DRD2 gene, polymorphisms, hypodopaminergia, reward deficiency, addictive and non-addictive behaviors

The inclusive transverse momentum distributions of charged hadrons and K0's produced in tagged photon-photon collisions, are measured and compared to model calculations up to a pT of 5 GeV/c. The relative abundance of K0's favor the inclusion of charm. © 1993.

We have searched for the reaction e+e-, where f is either an electron, muon, or charged pion, at s =29 GeV using the Mark II detector at the SLAC PEP storage ring. One candidate event is found while 2.3 events are expected from known processes. We would expect to see 11 events if the cross section for e+e- at s=29 GeV were enhanced by the factor of 4.7 which the ALEPH Collaboration reports for s=91 GeV. We also look for e+e- and e+e-, and for e+e-, using a similar analysis procedure, and see the number of events predicted by the standard model. © 1992 The American Physical Society.

We have searched for the reaction e+e-, where f is either an electron, muon, or charged pion, at s =29 GeV using the Mark II detector at the SLAC PEP storage ring. One candidate event is found while 2.3 events are expected from known processes. We would expect to see 11 events if the cross section for e+e- at s=29 GeV were enhanced by the factor of 4.7 which the ALEPH Collaboration reports for s=91 GeV. We also look for e+e- and e+e-, and for e+e-, using a similar analysis procedure, and see the number of events predicted by the standard model. © 1992 The American Physical Society.

We have searched for the annihilation of e+e- into the exclusive channels e and at s =29 GeV, using 226 and 133 pb-1, respectively, of data taken with the Mark II detector at the SLAC storage ring PEP. The resulting candidate sample is compatible with the expected background from pair production. Our analysis yields 95%-C.L. cross-section limits of e/

We have searched for the annihilation of e+e- into the exclusive channels e and at s =29 GeV, using 226 and 133 pb-1, respectively, of data taken with the Mark II detector at the SLAC storage ring PEP. The resulting candidate sample is compatible with the expected background from pair production. Our analysis yields 95%-C.L. cross-section limits of e/

We have tested QED to fourth order in the coupling constant in the large-Q2 region by studying four-lepton final states in e+e- interactions with the Mark II detector at the SLAC storage ring PEP (s=29 GeV). All four final-state particles were detected at large angles with respect to the beam axis. For an integrated luminosity of 205 pb-1, we observed ten e+e-e+e-, ten e+e-+-, and one events with opposite-charge pair masses greater than 1 GeV/c2. These events show good agreement with the complete 4 QED calculation. © 1990 The American Physical Society.

We present a new high-statistics measurement of the cross section for the process e+e-e+e-+- at a center-of-mass energy of 29 GeV for invariant pion-pair masses M(+-) between 350 MeV/c2 and 1.6 GeV/c2. We observe the f2(1270) and measure its radiative width to be 3.15±0.04±0.39 keV. We also observe an enhancement in the +- spectrum near 1 GeV. General agreement is found with unitarized models of the +- reaction that include final-state interactions. © 1990 The American Physical Society.

Using 203 pb-1 of data collected by the Mark II detector at the SLAC storage ring PEP, we have measured the radiative width of the for quasireal photons. The width is separately measured in the three reactions e+e-e+e-0+-,0; e+e-e+e-0+-; 0+-(0,), and e+e-e+e-0, giving a statistically weighted average two-photon width of=4.57±0.25±0.44 keV. As a byproduct of the study of the decay mode, we also measured the two-photon decay width of the a2(1320) as a2(1320)=1.03±0.13±0.21 keV. © 1990 The American Physical Society.

Using 203 pb-1 of data collected by the Mark II detector at the SLAC storage ring PEP, we have measured the radiative width of the for quasireal photons. The width is separately measured in the three reactions e+e-e+e-0+-,0; e+e-e+e-0+-; 0+-(0,), and e+e-e+e-0, giving a statistically weighted average two-photon width of=4.57±0.25±0.44 keV. As a byproduct of the study of the decay mode, we also measured the two-photon decay width of the a2(1320) as a2(1320)=1.03±0.13±0.21 keV. © 1990 The American Physical Society.

We have searched for a heavy charged lepton with an associated neutrino of nearly the same mass in e+e- annihilation data taken with the Mark II detector at a center-of-mass energy of 29 GeV. In order to suppress contamination from conventional two-photon reactions, this analysis uses a novel, radiative-tagging technique. Requiring the presence of an isolated, energetic photon allows a search for lepton doublets with mass splittings smaller than that previously accessible to experiment. No evidence for such a new lepton doublet has been found, enabling limits to be placed on allowed mass combinations. Mass splittings as low as 250-400 MeV/c2 are excluded for charged-lepton masses between 500 MeV/c2 and 10 GeV/c2. © 1990 The American Physical Society.

Data taken by the Mark II detector at the PEP storage ring was used to measure the rate of dilepton production in multihadronic events produced by e+e- annihilation at √s=29 GeV. We determine the probability that a hadron initially containing a b (b̄) quark decays to a positive (negative) lepton to be 0.17-0.08+0.15, with 90% confidence level limits of 0.06 and 0.38. © 1990.

We have studied the muon decay channel of the lepton with the presence of a photon in e+e- annihilation data at Ec.m.=29 GeV from the Mark II detector. Included in this study is the first direct measurement of radiative decay. We find the ratio of the measured branching fraction to the expected value from QED to be 1.03±0.42. © 1990 The American Physical Society.

We have studied the muon decay channel of the lepton with the presence of a photon in e+e- annihilation data at Ec.m.=29 GeV from the Mark II detector. Included in this study is the first direct measurement of radiative decay. We find the ratio of the measured branching fraction to the expected value from QED to be 1.03±0.42. © 1990 The American Physical Society.

We report a measurement of the lifetime of the B0 meson based upon 29-GeV e+e- annihilation data taken with the Mark II detector at the SLAC storage ring PEP. The B0 mesons are tagged by their decays into D*- and D*+, where the D*- is tagged by its decay into -D 0. We reconstruct the decay vertices of 15 B0-meson candidates and measure the B0 lifetime to be 1.20-0.360.14+0.52+0.16 psec. © 1990 The American Physical Society.

Data taken by the Mark II detector at the SLAC e+e- storage ring PEP was used to search for exclusive decays of D and B mesons into two charged leptons plus a charged pion or kaon. All possible charge and lepton combinations consistent with charge conservation were considered and no evidence for any signals was found. We obtain upper limits for the various branching ratios ranging from 2.5×10-3 to 9.2×10-3, at a 90% confidence level. Some of these limits can be used to constrain leptoquark masses in various models. © 1990 The American Physical Society.

Data taken by the Mark II detector at the SLAC e+e- storage ring PEP was used to search for exclusive decays of D and B mesons into two charged leptons plus a charged pion or kaon. All possible charge and lepton combinations consistent with charge conservation were considered and no evidence for any signals was found. We obtain upper limits for the various branching ratios ranging from 2.5×10-3 to 9.2×10-3, at a 90% confidence level. Some of these limits can be used to constrain leptoquark masses in various models. © 1990 The American Physical Society.

John H Peniston,1 Morris S Gold,2 Matthew S Wieman,3 Lawrence K Alwine4 1Feasterville Family Health Care Center, Feasterville, PA, 2Novartis Consumer Health, Inc, Parsippany, NJ, 3Endo Pharmaceuticals Inc, Malvern, PA, 4Downingtown Family Medicine, Downingtown, PA, USA Background: Topical diclofenac sodium 1% gel (DSG) has demonstrated efficacy and tolerability in patients with osteoarthritis (OA) of the knees or hands, including elderly patients and those with an increased risk of gastrointestinal, cardiovascular, and renal adverse events (AEs). Medications known to interact with diclofenac were disallowed in a clinical trial of DSG for knee OA; however, patients were not to be discontinued for intake of disallowed treatment, unless there was a safety issue. This post hoc analysis examined the frequency and type of AEs in patients who received DSG concomitantly with drugs known to have potential interactions with diclofenac. Materials and methods: This was a post hoc analysis of a randomized controlled trial of DSG for knee OA pain. Patients (n = 254) aged ≥ 35 years with OA in one or both knees, but with clinical OA symptoms in only one knee, administered DSG topically to the target knee four times daily (total dose, 16 g/d) for 12 weeks. Drugs with the potential for major or moderate drug–drug interactions (DDIs) were identified via Drugs.com. AE rates were compared in patients with versus those without ≥1 potential DDI. Results: At least one AE was experienced by 62.6% (107/171) of patients with ≥1 DDI and by 55.4% (46/83) of patients with no DDIs. Gastrointestinal AEs (upper and lower) were reported in 5.3% (9/171) and 7.2% (6/83), cardiovascular AEs in 4.7% (8/171) and 1.2% (1/83), renal AEs in 1.2% (2/171) and 0%, and hepatic AEs in 0% and 1.2% (1/83) of patients with ≥1 DDI compared with patients with no DDIs, respectively. Conclusion: Concurrent use of DSG with medications that had potential for major to moderate DDIs had little impact on the frequency of AEs in this population. Further research is needed to consider how factors such as dose, duration, and timing of concomitant drug administration may affect the likelihood of clinically evident AEs resulting from a potential DDI. Keywords: drug interactions, nonsteroidal anti-inflammatory drugs, topical administration, knee osteoarthritis

John H Peniston,1 Morris S Gold,2 Matthew S Wieman,3 Lawrence K Alwine41Feasterville Family Health Care Center, Feasterville, PA, 2Clinical Research and Biostatistics, Novartis Consumer Health Inc, Parsippany, NJ, 3Medical Affairs, Endo Pharmaceuticals Inc, Chadds Ford, PA, 4Downingtown Family Medicine, Downingtown, PA, USABackground: Adverse events associated with nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat knee and hand osteoarthritis may be more frequent in certain patient populations. Topical NSAIDs, such as diclofenac sodium 1% gel (DSG), have equivalent efficacy and fewer adverse events compared with oral NSAIDs. This post hoc analysis assessed the long-term tolerability of DSG in elderly patients and patients with an elevated risk of gastrointestinal, cardiovascular, and renal adverse events.Methods: Patients ≥ 35 years of age with knee osteoarthritis applied DSG (4 g) to one or both knees for 12 weeks during either of two primary studies and for 9 months during a long-term extension study. Other patients entered the long-term extension study directly and applied DSG for 12 months. Safety was assessed by reported adverse events. Subpopulations were defined based on age, or the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease.Results: The safety population consisted of 947 patients who received at least one dose of DSG during the primary or extension study. Patients aged < 65 years (68.2%) and ≥65 years (67.2%) experienced any adverse event at similar rates. The percentage of patients who experienced any adverse event was similar between patients with and without hypertension (65.5% versus 69.7%, respectively), type 2 diabetes mellitus (64.0% versus 68.2%), or cerebrovascular or cardiovascular disease (61.9% versus 68.5%). Among the 15 patients with all three comorbidities, the percentage of patients with any adverse event (53.3%) was less than that of patients who did not have all three comorbidities (68.0%).Conclusion: These results suggest that long-term DSG treatment is safe in patient subpopulations with an elevated risk of NSAID-related adverse events, such as the elderly and those with the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease.Keywords: diclofenac, nonsteroidal anti-inflammatory drugs, osteoarthritis, topical analgesic

We have made a detailed comparison of the charged-particle flow in three-jet events (e+e-qq»g) and radiative two-jet events (e+e-qq») from e+e- annihilation at Ec.m.=29 GeV. Accurate comparisons can be made because these two event types have similar topologies. In the angular region between the quark and antiquark jets, we observe substantially fewer charged tracks in the two-jet events than in the radiative three-jet events. © 1986 The American Physical Society.

The branching fraction for -5(0) is measured from data accumulated with the Mark II detector at PEP. Four events are observed with an estimated hadronic background of (0.03-0.02+0.04) events and a background from -30 of (0.05-0.04+0.07) events. This results in a measured branching fraction of (0.160.080.04)%. The candidate events are used to establish an upper limit of 125 MeV/c2 on the mass at the 95% confidence level. © 1985 The American Physical Society.

The Production has been investigated by the Mark II collaboration at the SLAC e+e- storage ring PEP. particles are reconstructed by their decay mode. The fragmentation function has been measured and found to be in good agreement with the Lund-model prediction. production has been measured for the first time in high-energy e+e- annihilation. There is evidence at the 3 level for Ds± decay into ± and ±. © 1988 The American Physical Society.

We use data taken by the Mark II detector at the SLAC storage ring PEP to study inclusive lepton production in e+e- annihilation at 29 GeV. From fits to the inclusive lepton momentum and transverse-momentum spectra we measure the semileptonic branching ratios for charm and bottom hadrons. We also determine with good precision the mean value of the bottom fragmentation function using both electron and muon samples. © 1988 The American Physical Society.

We have measured the branching fraction of -'-1/2 to be (22.3±0.6±1.4)% and the branching fraction of -'K*-1/2 to be (1.3±0.3±0.3)%. These values are consistent with the expectations for conventional decays of the . © 1986 The American Physical Society.

We report results of a search for events of the type e+e-jet+missing transverse momentum using the Mark II detector at PEP. Two candidate events were found, but both could come from known sources of background. A specific model for the origin of UA1 monojet events as the decay of a Z boson into two light Higgs bosons is eliminated by this search. © 1985 The American Physical Society.

The production of hyperons in e+e- annihilation has been measured as a function of their total momenta, transverse momenta, and the event thrust. The total production rate is 0.2130.0120.018 or per hadronic event. The observation of correlations in rapidity and angles for events with two detected decays supports fragmentation models with local baryon-number compensation. © 1985 The American Physical Society.

The branching ratios for + and -(n0), n>~1, have been measured to be 0.078 0.005 0.008 and 0.047 ± 0.005 ± 0.008, respectively. The total three-prong tau branching ratio is 0.128 ± 0.005 ± 0.008. Study of the 3± decay indicates that the three pions are predominantly from a JP=1+ state which decays through a 0± intermediate state in a relative s wave. The mass spectrum is suggestive of a resonance. © 1986 The American Physical Society.

The total momentum and transverse momentum spectra of electrons in e+e- annihilation at 29 GeV have been measured. The inclusive cross section is determined to be 14.4±1.6±5.2 pb for momenta greater than 2 GeV/c. The average semielectronic branching ratios of charm and bottom quarks are measured to be (6.3±1.2±2.1)% and (11.6±2.1±1.7)%, respectively. The fragmentation function for bottom quarks is determined to be peaked at high z, with zb=0.75±0.05±0.04. © 1983 The American Physical Society.

We have searched for the lepton-flavor-violating decay D0e in 204 pb-1 of e+e- annihilation data at Ec.m.=29 GeV from the Mark II detector. No candidates were found; we estimate an upper limit on the cross section times branching ratio of (e+e-D0,D0; inclusive)B(D0e)

We have used an electronic tracking system to measure the lifetime of D0 mesons produced in e+e- annihilation at 29 GeV. Based on a sample of 27 events, the lifetime is found to be (4.2-1.0+1.3 1.0) × 10-13 s. © 1984 The American Physical Society.

The average lifetime of bottom hadrons was measured with the Mark II vertex detector at the storage ring PEP. The lifetime was determined by measuring the impact parameters of leptons produced in bottom decays. τb=(12.0-3.6+4. 5±3.0)×10-13 sec was found. © 1983 The American Physical Society.

We have studied several features of the production of charged-hardon pairs by γγ collisions. We have measured the f0 partial width Γf0→γγ(Q2) for Q2 in the range 0

We use data from the Mark II experiment at PEP to search for the process B→h0X for mh0 between 50 and 210 MeV/c2. No evidence for the Higgs boson is seen in this mass range. The limit obtained rules out the standard Higgs boson for masses between 70 and 210 MeV/c2 and significantly constrains extensions of the Higgs sector. © 1989.

The branching fraction for -5(0) is measured from data accumulated with the Mark II detector at PEP. Four events are observed with an estimated hadronic background of (0.03-0.02+0.04) events and a background from -30 of (0.05-0.04+0.07) events. This results in a measured branching fraction of (0.160.080.04)%. The candidate events are used to establish an upper limit of 125 MeV/c2 on the mass at the 95% confidence level. © 1985 The American Physical Society.

The Production has been investigated by the Mark II collaboration at the SLAC e+e- storage ring PEP. particles are reconstructed by their decay mode. The fragmentation function has been measured and found to be in good agreement with the Lund-model prediction. production has been measured for the first time in high-energy e+e- annihilation. There is evidence at the 3 level for Ds± decay into ± and ±. © 1988 The American Physical Society.

The decay modes with multiple neutral mesons in the final states have been studied with the Mark II detector at the SLAC storage ring PEP. The branching ratio for the decay mode - 20 is found to be consistent with the theoretical expectation. However, the branching ratio for - 30 is found to be inconsistent with the theoretical prediction unless there are other decay modes with multiple neutral mesons in the final states. © 1987 The American Physical Society.

We have studied the energy-energy correlation in e+e- annihilation into hadrons at s =29 GeV using the Mark II detector at the SLAC storage ring PEP. We find to O(s2) that s=0.1580.0030.008 if hadronization is described by string fragmentation. Independent fragmentation schemes give s=0.100.14, and give poor agreement with the data. A leading-log shower fragmentation model is found to describe the data well. © 1988 The American Physical Society.

Four data sets collected with the Mark II detector during its operation at the SPEAR and PEP e+e- storage rings at SLAC are used to study the Bose-Einstein correlation between pairs and triplets of like-sign charged pions. The data sets represent four different regions of energy available for hadron production: the J at s =3.095 GeV, typical hadronic energy of 5 GeV in two-photon events, and annihilation in the energy regions s =47 GeV above the J, and s =29 GeV. The Bose-Einstein correlation is studied as a function of Q2, the four-momentum difference squared of the pair, and of Q32, an analogous quantity defined for triplets. After corrections for Coulomb effects and pion misidentification, pair analyses indicate a nearly full Bose-Einstein enhancement (1) in the J and the two-photon data, and about half the maximum value in the two higher-energy data sets. The pair analysis parameter r lies within a band of ±0.1 fm around 0.7 fm and is essentially the same for all four data sets. Pion triplet analyses give consistent results for the triplet parameters 3 and r3. In an attempt to investigate the shape of the pion source, we also study the Bose-Einstein correlation in pion pairs using two-dimensional distributions in components of Q2. © 1989 The American Physical Society.

Multihadronic e+e- annihilation events at a center-of-mass energy of 29 GeV have been studied with both the original (PEP 5) Mark II and the upgraded Mark II detectors. Detector-corrected distributions from global shape analyses such as aplanarity, Q2-Q1, sphericity, thrust, minor value, oblateness, and jet masses, and inclusive charged-particle distributions including x, rapidity, p, and particle flow are presented. These distributions are compared with predictions from various multihadron event models which use leading-logarithmic shower evolution or QCD matrix elements at the parton level and string or cluster fragmentation for hadronization. The new generation of parton-shower models gives, on the average, a better description of the data than the previous parton-shower models. The energy behavior of these models is compared to existing e+e- data. The predictions of the models at a center-of-mass energy of 93 GeV, roughly the expected mass of the Z0, are also presented. © 1988 The American Physical Society.

We update our previous analysis of the 3±01/2 decay mode by the addition of new data to obtain an improved upper limit on the 1/2 mass of 143 MeV/c2 at the 95% confidence level. © 1985 The American Physical Society.