text:
Figure 1. PRISMA Flowchart of Search Strategy and Study Selection
Figure 2. Risk of Bias Assessment Summary
The + indicates low risk of bias; −, high risk of bias; and ?, unclear risk of bias.
Figure 3. Network Graphs and Forest Plots of Network Meta-analysis Results for Patient-Relevant Treatment Outcomes (Any Reported Adverse Event or Skin-Related Adverse Event) Irrespective of Antibiotic Treatment Dose or Duration
A, Analysis includes complete and partial responders in 6 randomized clinical trials (RCTs) of 6 antibiotic agents and 908 patients. B, Analysis includes 14 RCTs, 9 antibiotic agents, and 1793 patients. C, Analysis includes 9 RCTs, 6 antibiotic agents, and 1211 patients. OR indicates odds ratio; numbers in network graphs, number of comparisons.
Figure 4. Network Graphs and Forest Plots of Network Meta-analysis Results for Patient-Relevant Treatment Outcomes (Gastrointestinal Tract and Hematologic Adverse Events or Jarisch-Herxheimer–Like Reaction) Irrespective of Antibiotic Treatment Dose or Duration
A, Analysis includes 8 randomized clinical trials (RCTs), 6 antibiotic agents, and 926 patients. B, Analysis includes 3 RCTs, 3 antibiotic agents, and 437 patients; C, Analysis includes 7 RCTs, 7 antibiotic agents, and 710 patients. OR indicates odds ratio; numbers in network graphs, number of comparisons.
Table. Summary of Findings for Antibiotics Compared Irrespective of Dose and Durationa
eTable 1. Definition of Treatment Response and Assessment of Treatment Response in the Individual Studies
eTable 2. Study Characteristics
eTable 3. Summary of Findings Table: Different Treatment Regimens
eFigure 1. Outcome: Response to Treatment
eFigure 2. Outcome: Any Reported Adverse Events
eFigure 3. Outcome: Any Skin-Related Adverse Events
eFigure 4. Outcome: Any Gastrointestinal Adverse Events
eFigure 5. Outcome: Jarisch-Herxheimer–like Reactions
eAppendix 1. The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions
eAppendix 2. Differences Between Protocol and Review
eAppendix 3. Search Strategy Database(s) in MEDLINE(R) (via Ovid on 2015-11-24)
Altpeter E, Zimmermann H, Oberreich J, Péter O, Dvořák C; Swiss Sentinel Surveillance Network. Tick related diseases in Switzerland, 2008 to 2011. Swiss Med Wkly. 2013;143:w13725.PubMedGoogle Scholar
Bacon RM, Kugeler KJ, Mead PS; Centers for Disease Control and Prevention (CDC). Surveillance for Lyme disease—United States, 1992-2006. MMWR Surveill Summ. 2008;57(10):1-9.PubMedGoogle Scholar
Berglund J, Eitrem R, Ornstein K, et al. An epidemiologic study of Lyme disease in southern Sweden. N Engl J Med. 1995;333(20):1319-1327. doi:10.1056/NEJM199511163332004PubMedGoogle ScholarCrossref
Hubálek Z. Epidemiology of Lyme borreliosis. Curr Probl Dermatol. 2009;37:31-50. doi:10.1159/000213069PubMedGoogle ScholarCrossref
Ni XB, Jia N, Jiang BG, et al. Lyme borreliosis caused by diverse genospecies of Borrelia burgdorferi sensu lato in northeastern China. Clin Microbiol Infect. 2014;20(8):808-814. doi:10.1111/1469-0691.12532PubMedGoogle ScholarCrossref
Sykes RA, Makiello P. An estimate of Lyme borreliosis incidence in Western Europe. J Public Health (Oxf). 2017;39(1):74-81.PubMedGoogle Scholar
Aberer E, Kehldorfer M, Binder B, Schauperi H. The outcome of Lyme borreliosis in children. Wien Klin Wochenschr. 1999;111(22-23):941-944.PubMedGoogle Scholar
Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34(1):1-9.PubMedGoogle Scholar
Huppertz HI, Böhme M, Standaert SM, Karch H, Plotkin SA. Incidence of Lyme borreliosis in the Würzburg region of Germany. Eur J Clin Microbiol Infect Dis. 1999;18(10):697-703. doi:10.1007/s100960050381PubMedGoogle ScholarCrossref
Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet. 2012;379(9814):461-473. doi:10.1016/S0140-6736(11)60103-7PubMedGoogle ScholarCrossref
Eriksson P, Schröder MT, Niiranen K, Nevanlinna A, Panelius J, Ranki A. The many faces of solitary and multiple erythema migrans. Acta Derm Venereol. 2013;93(6):693-700. doi:10.2340/00015555-1549PubMedGoogle ScholarCrossref
Hofmann H. The variable spectrum of cutaneous Lyme borreliosis: diagnosis and therapy [in German]. Hautarzt. 2012;63(5):381-389. doi:10.1007/s00105-011-2256-0PubMedGoogle ScholarCrossref
Nadelman RB, Wormser GP. Recognition and treatment of erythema migrans: are we off target? Ann Intern Med. 2002;136(6):477-479. doi:10.7326/0003-4819-136-6-200203190-00012PubMedGoogle ScholarCrossref
Shapiro ED. Clinical practice: Lyme disease. N Engl J Med. 2014;370(18):1724-1731. doi:10.1056/NEJMcp1314325PubMedGoogle ScholarCrossref
Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002;136(6):421-428. doi:10.7326/0003-4819-136-6-200203190-00005PubMedGoogle ScholarCrossref
Stanek G, Fingerle V, Hunfeld KP, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect. 2011;17(1):69-79. doi:10.1111/j.1469-0691.2010.03175.xPubMedGoogle ScholarCrossref
Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134. doi:10.1086/508667PubMedGoogle ScholarCrossref
Strle F, Stanek G. Clinical manifestations and diagnosis of Lyme borreliosis. Curr Probl Dermatol. 2009;37:51-110. doi:10.1159/000213070PubMedGoogle ScholarCrossref
van den Wijngaard CC, Hofhuis A, Harms MG, et al. The burden of Lyme borreliosis expressed in disability-adjusted life years. Eur J Public Health. 2015;25(6):1071-1078. doi:10.1093/eurpub/ckv091PubMedGoogle ScholarCrossref
Karimkhani C, Dellavalle RP, Coffeng LE, et al. Global skin disease morbidity and mortality: an update from the Global Burden of Disease Study 2013. JAMA Dermatol. 2017;153(5):406-412. doi:10.1001/jamadermatol.2016.5538PubMedGoogle ScholarCrossref
Loewen PS, Marra CA, Marra F. Systematic review of the treatment of early Lyme disease. Drugs. 1999;57(2):157-173. doi:10.2165/00003495-199957020-00003PubMedGoogle ScholarCrossref
Müllegger RR, Glatz M. Skin manifestations of lyme borreliosis: diagnosis and management. Am J Clin Dermatol. 2008;9(6):355-368. doi:10.2165/0128071-200809060-00002PubMedGoogle ScholarCrossref
Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet. 1990;336(8728):1404-1406. doi:10.1016/0140-6736(90)93103-VPubMedGoogle ScholarCrossref
Dattwyler RJ, Grunwaldt E, Luft BJ. Clarithromycin in treatment of early Lyme disease: a pilot study. Antimicrob Agents Chemother. 1996;40(2):468-469.PubMedGoogle ScholarCrossref
Schmidt BL, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagn Microbiol Infect Dis. 1995;21(3):121-128. doi:10.1016/0732-8893(95)00027-8PubMedGoogle ScholarCrossref
Wahlberg P, Nyman D. Penicillin V treatment in erythema migrans can give a false security [in Swedish]. Lakartidningen. 2006;103(9):668.PubMedGoogle Scholar
Eliassen KE, Lindbaek M, Berild D, Hjortdahl P, Fetveit A. [First-choice treatment for erythema migrans is still penicillin] [in Norwegian]. Tidsskr Nor Laegeforen. 2008;128(15):1681.PubMedGoogle Scholar
Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9):1103-1135. doi:10.1586/14787210.2014.940900PubMedGoogle ScholarCrossref
Evison J, Aebi C, Francioli P, et al. Lyme disease part 2: clinic and treatment [in French]. Rev Med Suisse. 2006;2(60):925-928, 930-934.PubMedGoogle Scholar
Dersch R, Toews I, Sommer H, Rauer S, Meerpohl JJ. Methodological quality of guidelines for management of Lyme neuroborreliosis. BMC Neurol. 2015;15:242. doi:10.1186/s12883-015-0501-3PubMedGoogle ScholarCrossref
Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784. doi:10.7326/M14-2385PubMedGoogle ScholarCrossref
Torbahn G, Hofmann H, Allert R, et al. Efficacy and safety of pharmacological agents in the treatment of erythema migrans in early Lyme borreliosis-systematic review protocol. Syst Rev. 2016;5:73. doi:10.1186/s13643-016-0251-3PubMedGoogle ScholarCrossref
World Health Organization. International Clinical Trials Registry Platform. http://www.who.int/ictrp/search/en. Accessed July 2018.
Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration Version 5.1.0. Chapter 9: analysing data and undertaking meta-analyses by Deeks JJ, Higgins JPT, Altman DG. https://handbook-5-1.cochrane.org/chapter_9/9_analysing_data_and_undertaking_meta_analyses.htm. Updated March 2011. Accessed December 16, 2017.
Puhan MA, Schünemann HJ, Murad MH, et al; GRADE Working Group. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ. 2014;349:g5630. doi:10.1136/bmj.g5630PubMedGoogle ScholarCrossref
Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JPT. Evaluating the quality of evidence from a network meta-analysis. PLoS One. 2014;9(7):e99682. doi:10.1371/journal.pone.0099682PubMedGoogle ScholarCrossref
Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3, rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-406. doi:10.1016/j.jclinepi.2010.07.015PubMedGoogle ScholarCrossref
Dias S, Welton NJ, Sutton AJ, Ades AE. Evidence synthesis for decision making 1: introduction. Med Decis Making. 2013;33(5):597-606. doi:10.1177/0272989X13487604PubMedGoogle ScholarCrossref
Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades AE. Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. Med Decis Making. 2013;33(5):641-656. doi:10.1177/0272989X12455847PubMedGoogle ScholarCrossref
Rücker G. Network meta-analysis, electrical networks and graph theory. Res Synth Methods. 2012;3(4):312-324. doi:10.1002/jrsm.1058PubMedGoogle ScholarCrossref
Rücker G, Schwarzer G. Reduce dimension or reduce weights? comparing two approaches to multi-arm studies in network meta-analysis. Stat Med. 2014;33(25):4353-4369. doi:10.1002/sim.6236PubMedGoogle ScholarCrossref
German Borreliosis Society. Diagnosis and treatment of Lyme borreliosis. http://www.borreliose-gesellschaft.de/Texte/Leitlinien.pdf. Published 2011. Accessed July 5, 2018.
Senn S. Trying to be precise about vagueness. Stat Med. 2007;26(7):1417-1430. doi:10.1002/sim.2639PubMedGoogle ScholarCrossref
Netmeta. Network meta-analysis using frequentist methods by Rücker G, Schwarzer G, Krahn U, Koenig J. https://CRAN.R-project.org/package=netmeta. Updated 2017. Accessed December 16, 2017.
R Core Team. R Foundation for Statistical Computing Vienna, Austria, 2017. R: a language and environment for statistical computing. https://www.R-project.org/. Accessed December 16, 2017.
Rücker G, Schwarzer G. Automated drawing of network plots in network meta-analysis. Res Synth Methods. 2016;7(1):94-107. doi:10.1002/jrsm.1143PubMedGoogle ScholarCrossref
Unnebrink K, Windeler J. Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases. Stat Med. 2001;20(24):3931-3946. doi:10.1002/sim.1149PubMedGoogle ScholarCrossref
Cerar D, Cerar T, Ruzić-Sabljić E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med. 2010;123(1):79-86. doi:10.1016/j.amjmed.2009.05.011PubMedGoogle ScholarCrossref
Stupica D, Lusa L, Ruzić-Sabljić E, Cerar T, Strle F. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis. 2012;55(3):343-350. doi:10.1093/cid/cis402PubMedGoogle ScholarCrossref
Stupica D, Lusa L, Maraspin V, et al. Correlation of culture positivity, PCR positivity, and burden of borrelia burgdorferi sensu lato in skin samples of erythema migrans patients with clinical findings. PLoS One. 2015;10(9):e0136600. doi:10.1371/journal.pone.0136600PubMedGoogle ScholarCrossref
Aberer E, Kahofer P, Binder B, Kinaciyan T, Schauperl H, Berghold A. Comparison of a two- or three-week regimen and a review of treatment of erythema migrans with phenoxymethylpenicillin. Dermatology. 2006;212(2):160-167. doi:10.1159/000090657PubMedGoogle ScholarCrossref
Barsic B, Maretic T, Majerus L, Strugar J. Comparison of azithromycin and doxycycline in the treatment of erythema migrans. Infection. 2000;28(3):153-156. doi:10.1007/s150100050069PubMedGoogle ScholarCrossref
Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a double-blind, randomized, controlled trial. Ann Intern Med. 1996;124(9):785-791. doi:10.7326/0003-4819-124-9-199605010-00002PubMedGoogle ScholarCrossref
Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents Chemother. 1995;39(3):661-667. doi:10.1128/AAC.39.3.661PubMedGoogle ScholarCrossref
Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme disease. Am J Med. 1992;92(4):396-403. doi:10.1016/0002-9343(92)90270-LPubMedGoogle ScholarCrossref
Nadelman RB, Luger SW, Frank E, Wisniewski M, Collins JJ, Wormser GP. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med. 1992;117(4):273-280. doi:10.7326/0003-4819-117-4-273PubMedGoogle ScholarCrossref
Steere AC, Hutchinson GJ, Rahn DW, et al. Treatment of the early manifestations of Lyme disease. Ann Intern Med. 1983;99(1):22-26. doi:10.7326/0003-4819-99-1-22PubMedGoogle ScholarCrossref
Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M. Azithromycin versus doxycycline for treatment of erythema migrans: clinical and microbiological findings. Infection. 1993;21(2):83-88. doi:10.1007/BF01710737PubMedGoogle ScholarCrossref
Weber K, Wilske B, Preac-Mursic V, Thurmayr R. Azithromycin versus penicillin V for the treatment of early Lyme borreliosis. Infection. 1993;21(6):367-372. doi:10.1007/BF01728915PubMedGoogle ScholarCrossref
Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138(9):697-704. doi:10.7326/0003-4819-138-9-200305060-00005PubMedGoogle ScholarCrossref
Breier F, Kunz G, Klade H, Stanek G, Aberer E. Erythema migrans: three weeks treatment for prevention of late Lyme borreliosis. Infection. 1996;24(1):69-72. doi:10.1007/BF01780662PubMedGoogle ScholarCrossref
Hansen K, Hovmark A, Lebech AM, et al. Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in vivo animal susceptibility study and a clinical trial in patients with erythema migrans. Acta Derm Venereol. 1992;72(4):297-300.PubMedGoogle Scholar
Strle F, Ruzic E, Cimperman J. Erythema migrans: comparison of treatment with azithromycin, doxycycline and phenoxymethylpenicillin. J Antimicrob Chemother. 1992;30(4):543-550. doi:10.1093/jac/30.4.543PubMedGoogle ScholarCrossref
Weber K, Preac-Mursic V, Wilske B, Thurmayr R, Neubert U, Scherwitz C. A randomized trial of ceftriaxone versus oral penicillin for the treatment of early European Lyme borreliosis. Infection. 1990;18(2):91-96. doi:10.1007/BF01641422PubMedGoogle ScholarCrossref
Eliassen KE, Reiso H, Berild D, Lindbæk M. Comparison of phenoxymethylpenicillin, amoxicillin, and doxycycline for erythema migrans in general practice: a randomized controlled trial with a 1-year follow-up [published online March 2, 2018]. Clin Microbiol Infect. doi:10.1016/j.cmi.2018.02.028PubMedGoogle Scholar
Strle F, Stupica D, Bogovič P, Visintainer P, Wormser GP. Is the risk of early neurologic Lyme borreliosis reduced by preferentially treating patients with erythema migrans with doxycycline? Diagn Microbiol Infect Dis. 2018;91(2):156-160. doi:10.1016/j.diagmicrobio.2018.01.025PubMedGoogle ScholarCrossref
Dersch R, Freitag MH, Schmidt S, Sommer H, Rauer S, Meerpohl JJ. Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis—a systematic review. Eur J Neurol. 2015;22(9):1249-1259. doi:10.1111/ene.12744PubMedGoogle ScholarCrossref
Cadavid D, Auwaerter PG, Rumbaugh J, Gelderblom H. Antibiotics for the neurological complications of Lyme disease. Cochrane Database Syst Rev. 2016;12:CD006978.PubMedGoogle Scholar
Hofmann H, Fingerle V, Hunfeld KP, et al; Consensus group. Cutaneous Lyme borreliosis: guideline of the German Dermatology Society. Ger Med Sci. 2017;15:Doc14.PubMedGoogle Scholar
National Institute for Health and Care Excellence (NICE). National Guideline Centre. Lyme disease: diagnosis and management. Evidence review for the management of erythema migrans. https://www.nice.org.uk/guidance/ng95/evidence/d-management-of-erythema-migrans-pdf-4792271010. Published April 2018. Accessed July 05, 2018.
Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a review. JAMA. 2016;315(16):1767-1777. doi:10.1001/jama.2016.2884PubMedGoogle ScholarCrossref
Kanters S, Ford N, Druyts E, Thorlund K, Mills EJ, Bansback N. Use of network meta-analysis in clinical guidelines. Bull World Health Organ. 2016;94(10):782-784. doi:10.2471/BLT.16.174326PubMedGoogle ScholarCrossref
Antibiotic Use, Overuse, Resistance, Stewardship Dermatology Infectious Diseases Tick-Borne Illness
Torbahn G, Hofmann H, Rücker G, et al. Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis. JAMA Dermatol. 2018;154(11):1292–1303. doi:10.1001/jamadermatol.2018.3186
Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis
Gabriel Torbahn, MPH1; Heidelore Hofmann, MD2; Gerta Rücker, PhD1,3; et al Karin Bischoff, MSc1; Michael H. Freitag, MD, MPH4; Rick Dersch, MD5; Volker Fingerle, MD6; Edith Motschall, MSc3; Joerg J. Meerpohl, MD1; Christine Schmucker, PhD1
1Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
2Department of Dermatology and Allergology, Technical University of Munich, München, Germany
3Division of General Practice and Family Medicine, Department of Health Services Research, University of Oldenburg, Oldenburg, Germany
4Department of Neurology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
5National Reference Centre for Borrelia, Bavarian Health and Food Safety Authority, Oberschleißheim, Germany
6Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
JAMA Dermatol. 2018;154(11):1292-1303. doi:10.1001/jamadermatol.2018.3186
Question What are the most effective and safest antibiotic treatments of early cutaneous Lyme borreliosis?
Findings This network meta-analysis that included 2532 patients did not detect any significant differences in treatment response by antibiotic agent, dose, or duration. There were also no differences in the effect sizes among antibiotic agents and treatment modalities in treatment-related adverse outcomes, which were generally mild to moderate, and treatment failures were rare.
Meaning Neither the antibiotic agent nor the treatment modality contributes to comparative effectiveness or drug-related adverse outcomes in early cutaneous Lyme borreliosis.
Importance Controversies about the choice of antibiotic agent and treatment modality exist in the management of erythema migrans in early cutaneous Lyme borreliosis (LB).
Objective To conduct a network meta-analysis (NMA) of all randomized clinical trials on various antibiotic agents and treatment modalities in early cutaneous LB.
Data Sources Electronic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception until July 2017. The reference lists of the included studies were hand searched, authors were contacted, and ongoing trials were searched at ClinicalTrials.gov.
Study Selection One reviewer screened the titles and abstracts of the 9975 reports identified by the electronic searches. Full-text copies of 161 potentially relevant articles were obtained, and 2 reviewers independently assessed those articles for inclusion. Adults with a physician-confirmed early localized skin infection who were treated with antibiotics of any dose or duration were included.
Data Extraction and Synthesis Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analyses on treatment effects and adverse outcomes were calculated with a frequentist approach using the R package netmeta. The Grading of Recommendations Assessment, Development and Evaluation guidance for NMA was used to assess the certainty of evidence.
Main Outcomes and Measures Treatment effects for response to treatment (resolution of symptoms) and treatment-related adverse events.
Results Overall, 19 studies (2532 patients) were included. The mean patient age ranged between 37 and 56 years, and the percentage of female patients ranged from 36% to 60%. The antibiotics investigated were doxycycline, cefuroxime axetil, ceftriaxone, amoxicillin, azithromycin, penicillin V, and minocycline. Pooled effect sizes from NMAs did not suggest any significant differences in treatment response by antibiotic agent (eg, amoxicillin vs doxycycline odds ratio, 1.26; 95% CI, 0.41-3.87), dose, or duration (eg, doxycycline, 200 mg/d for 3 weeks, vs doxycycline, 200 mg/d for 2 weeks, odds ratio, 1.28; 95% CI, 0.49-3.34). Treatment failures were rare at both 2 months (4%; 95% CI, 2%-5%) and 12 months (2%, 95% CI, 1%-3%) after treatment initiation. There were also no differences in the effect sizes among antibiotic agents and treatment modalities for treatment-related adverse outcomes, which were generally mild to moderate. Certainty of evidence was categorized as low and very low mostly because of imprecision, indirectness, and study limitations (high risk of bias) of the included studies.
Conclusions and Relevance This NMA suggests that neither the antibiotic agent nor treatment modality contributed to comparative effectiveness or drug-related adverse outcomes. This finding is relevant for physicians treating patients with LB and for patient decision making.
Lyme borreliosis (LB) is a disease caused by the spirochete Borrelia burgdorferi and transmitted by tick bites in most northern hemisphere countries of Europe, North America, and Asia.1-5 Countries in Western Europe have a large variance in incidence rates. The highest rates of LB have been reported in southern Sweden, with 464 per 100 000 person-years, and the lowest rates have been reported in Italy, with 0.001 per 100 000 person-years.6 The population-weighted incidence rate in Western Europe has been estimated by 1 study6 to be 22.04 per 100 000 person-years.
Early localized manifestations of LB include erythema migrans (EM) and, more seldom, borrelial lymphocytoma. Erythema migrans is detected in approximately 70% to 90% of patients with LB7-10 and can have a range of appearances, including the classic bull's-eye lesion, but atypical lesions are also common.11-15 Erythema migrans typically occurs at the site of the tick bite 3 to 32 days after the bite.12,14,16 Most individuals show a single lesion although approximately 10% to 20% of patients with LB show multiple EM lesions (MEM), which are caused by hematogenic dissemination of the bacteria via the bloodstream into the skin. Early disseminated manifestations of LB include neuroborreliosis (affecting 10%-20% of patients with LB)3,9 and heart problems (affecting 4%-10% of patients with LB).17 Late manifestations (affecting 2%-10% of patients with LB) may involve the joints18 but may also involve the nervous system or the skin. Lyme borreliosis has a substantial disease burden of 10.6 disability-adjusted life-years (DALYs) per 100 000 persons based on the incidence rate in northern Europe (Netherland) in 2010, with 9.1 DALYs for persisting symptoms, 0.9 DALYs for disseminated LB, and 0.6 DALYs for EM.19 Compared with other more common cutaneous diseases, EM has a low disease burden. For example, an update from the Global Burden of Disease Study 201320 reported 55 DALYs for viral skin diseases and 16 DALYs for cellulitis.
Patients with early cutaneous manifestations of LB are generally treated with antibiotics to eliminate the spirochete to cure immediate disease and to prevent late manifestations. The broad-spectrum antibiotic doxycycline is the mainstay of therapy for cutaneous manifestations of LB.21 Other first-line antibacterial agents are phenoxymethylpenicillin (also known as penicillin V), amoxicillin, or cefuroxime axetil.22-24 However, some treatment failures have been reported with all antibiotic agents in use.25-27 In particular, undertreated infections may resurface and result in progression and dissemination to other organs, especially the nervous system and joints, causing long-term morbidity and costs.28-30 Hence, the aim of the present study was to conduct a systematic review of all randomized clinical trials focused on treatment response and drug-related adverse outcomes of various antibiotic regimens in adults with early cutaneous LB to provide evidence for the development of clinical practice guidelines and individual patient decision making.
Reporting Guideline and Protocol
This research was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for systematic reviews incorporating network meta-analyses (NMA) of health care interventions (eAppendix 1 in the Supplement).31 The methods of this systematic review were prespecified in a protocol published in 2016.32 Modifications to that protocol are described in eAppendix 2 in the Supplement.
Search Strategies and Inclusion Criteria
To identify eligible studies, we conducted electronic searches in Ovid MEDLINE, Ovid MEDLINE in Process & Other Non-Indexed Citations, Ovid MEDLINE daily update, Ovid Embase, and the Cochrane Central Register of Controlled Trials (via the Cochrane Library) from inception until November 2015. An update search was performed July 2017. The search strategy was based on combinations of medical subject headings and keywords and was not restricted to any specific language. The search strategy used in Ovid MEDLINE is given in eAppendix 3 in the Supplement. Search strategies for the other databases were modified to meet the requirements of each database. In addition, we hand-searched reference lists of included studies and contacted authors. Searches for ongoing trials or trials completed but not published were conducted on ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform.33 One reviewer (G.T.) screened the titles and abstracts of all references identified by electronic searches. We obtained full-text copies of all potentially relevant articles, and 2 reviewers (G.T., H.H., K.B., M.H.F., or C.S.) independently assessed those articles for inclusion. Conflicts were resolved by discussion. The randomized clinical trials considered for this review included those studying adults with a clinically (physician-confirmed) early localized skin infection who were treated with antibiotics of any dose for any duration.
We extracted data on patients (eg, number of patients included and randomized, and the proportion of patients receiving a diagnosis of EM or MEM), interventions (eg, antibiotic agent, dosage, length of treatment), and outcomes (response to treatment and any treatment-related adverse event). For the outcome "response to treatment," we conducted 2 analyses. First, we combined complete responders and partial responders and compared them with treatment failures (persistent EM, disseminated disease, or both). We then combined partial responders and treatment failures and compared them with complete responders. The definition and assessment of response to treatment as described in the individual studies are given in eTable 1 in the Supplement. All reported adverse events were extracted according to the definitions of the primary studies, and individual participants served as the unit of analysis. Because repeated adverse events can occur in the same participant, we considered the number of individuals with at least 1 event of a type, rather than the total number of any adverse event. In addition, we also categorized all adverse events involving the skin or gastrointestinal tract or hematologic or Jarisch-Herxheimer–like reactions using the individual participant as the unit of analysis. Outcome data for which only the number of events, and not the number of participants, was reported were not included.
Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation
Risk of bias was assessed according to the method described in the Cochrane Handbook for Systematic Reviews of Interventions.34 The following domains were considered: randomization sequence generation; allocation concealment; masking (blinding) of participants, trial personal, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias (ie, bias due to problems not covered elsewhere).
The certainty of evidence for the outcomes response to treatment (≥12 months following start of treatment) and any treatment-related adverse event was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for NMA, which is associated with specific comparisons, including estimates from direct and indirect comparisons.35,36 In brief, our certainty assessment addressed study limitations (risk of bias), incoherence (differences between direct and indirect estimates of effect as defined by the P values of z tests and the size and overlap of 95% CIs of direct and indirect estimates), imprecision (95% CIs that were wide or included or were close to a null effect around the point estimate from the indirect comparison), inconsistency (differences in estimates of effect across studies that assessed the same comparison), and indirectness (in an NMA, indirectness expresses concerns from indirect comparisons, a so-called intransitivity measure).35,37 Indirect estimates were potentially further downgraded for intransitivity (ie, differences in patient characteristics, differing (co-)intervention, differing extent to which intervention of interest was optimally administered, differing comparator, and differences in measurement of outcome). In the event of coherent direct and indirect effect estimates, the higher rating was assigned to the NMA estimate. On the basis of these criteria, the certainty of the evidence for each comparison and outcome was categorized as high, moderate, low, or very low. The results of the NMA are presented as suggested by the GRADE Working Group,35,36 in the Table. Data extraction, risk of bias assessment, and the GRADE assessment were independently conducted by the aforementioned reviewers.
We used NMA for synthesizing information from numerous studies addressing the same outcomes but involving different interventions.38,39 For a given comparison (A vs B), direct evidence is usually provided by studies that compare these treatments directly. In addition, indirect evidence for the A vs B comparison can be provided by synthesizing studies that compare A vs C and B vs C. Hence, NMA combines direct and indirect evidence across a network of studies into a single effect size. For the present NMA, we used a frequentist approach based on the graph-theoretical method by Rücker et al.40,41 For the main analyses, doxycycline irrespective of dose or duration was chosen as the reference treatment. In addition, analyses to investigate the different treatment modalities were conducted using administration of doxycycline, 200 mg/d for 14 to 15 days, as the reference treatment.42 Estimations of treatment effects were calculated based on a random effects model43 using the R package netmeta.44,45 The netmeta function netgraph was used to generate network plots.46
The results for the response to treatment outcome are presented for both short-term (≤2 months following start of treatment) and long-term follow-up (≥12 months following start of treatment). Treatment effects are expressed as odds ratios (ORs) with 95% CIs. Overall, when significant heterogeneity was found among comparable studies (I2 for heterogeneity >50%), pooled estimates were not provided (which was, however, not the case in the present study). Data for the response to treatment outcome were analyzed, if possible, on an intention-to-treat basis.47 For adverse events, we conducted a complete case analysis (ie, including only participants assessed at each specific follow-up time).
Literature Search and Selection Process
After elimination of duplicates among databases, we screened 9975 references, of which the full text was evaluated for 161 references (Figure 1). We included 19 randomized clinical trials (2532 patients) that compared different antibiotic agents, treatment strategies, or both, of which 17 studies were included in the NMA.23,48-65
Study Characteristics
The main study characteristics are presented in eTable 2 in the Supplement. Across trials, the mean patient age ranged between 37 and 56 years, and the percentage of female patients ranged from 36% to 60%. Four studies enrolled solely patients with solitary EM,48-50,65 8 studies included mixed populations showing solitary EM and MEM (indirect population, patients with MEM<19%),23,52-54,56,58,59,63 and 7 studies did not provide detailed information on the included patient population.51,55,57,60-62,64 The included studies were conducted with outpatients in the United States (7 studies, 1049 patients),17,23,53-57 Slovenia (5 studies, 806 patients),48-50,58,63 Austria (2 studies, 162 patients),51,61 Germany (2 studies, 139 patients),59,64 Croatia (1 study, 88 patients),52 Sweden (1 study, 100 patients)62 and Norway (1 study, 188 patients).65 Median follow-up from treatment initiation was 12 months (range, 6 weeks to 30 months). All studies were active comparator studies, that is, none included a placebo control. Doxycycline (administered at various dosages and durations) was the most frequently investigated drug, with 909 patients assigned.23,48,49,52,54-56,58,60,63,65 Other antibiotics investigated were azithromycin,50,52,53,55,58,59,63 penicillin V,51,59,61-65 cefuroxime axetil,48,50,54,56 and amoxicillin,50,53,65 whereas ceftriaxone64 or ceftriaxone in combination with doxycycline60 or with minocycline61 were investigated in only 1 trial each. Two studies included patients receiving probenecid in addition to amoxicillin to increase the concentration of amoxicillin.23,55
Assessment of Risk of Bias
The results of the risk of bias assessment are provided in Figure 2. Five studies were judged to have a high risk of selection bias because of major limitations in the randomization process.48-51,63 In another 4 studies, patients, clinicians, and outcome assessors were aware of the treatment group, leading to a high risk of performance and detection bias.52,59,61,64 Five studies were associated with a low risk of bias for random sequence generation and adequate blinding of outcome assessors.53,54,56,60,65 Selective reporting could not be sufficiently assessed because of missing information regarding important outcome measures (ie, no study protocol was prepublished, or outcome measures were neither predefined nor clearly described). Five studies were poorly reported overall, making an adequate risk of bias assessment impossible.23,55,57,58,62
Response to Treatment
When antibiotic agents were compared irrespective of dose and duration, pooled effect sizes did not suggest significant differences in treatment response among agents for up to 2 months after treatment initiation (10 studies, 8 agents [nodes], and 1435 patients)17,24,48,52-56,59,61 nor at 12 or more months after treatment initiation (6 studies, 6 agents [nodes], 908 patients, and low and very low certainty) (Figure 3A and Table).48,50,59,60,63,65 Overall, more than 80% of patients showed a treatment response, 84% (95% CI, 80%-88%) at 2 or fewer months after treatment initiation and 80% (95% CI, 74%-85%) at 12 or more months following treatment initiation. The reasons for the treatment failures were mainly disseminated manifestations, including neuroborreliosis or damage of the nervous system (≤2 months, 4% [95% CI, 2%-5%]; ≥12 months, 2% [95% CI, 1%-3%]). For 136 of 908 patients (approximately 15%), treatment response could not be categorized; therefore, these data are missing in the response definition. Additional analyses showed that dosage and duration also did not influence effectiveness expressed as response to treatment, neither up to 2 months after treatment initiation (6 studies, 9 modalities [nodes], and 934 patients)23,48,49,52,55,60 nor at 12 or more months after treatment initiation (8 studies, 10 modalities [nodes], and 1235 patients)48-51,59,60,65,66 (eFigure 1 in the Supplement; individual study data are given in eTable 3 in the Supplement). Overall, NMA findings for the response to treatment outcome were also similar regardless of the definition of treatment responders (ie, combining complete responders and partial responders vs treatment failures or combining partial responders and treatment failures vs complete responders) or the definition of EM (combining patients with localized EM and MEM vs patients with localized EM) although these results are not shown in a figure.
Any Reported Adverse Event
Adverse events occurred in 31% (95% CI, 25%-37%) of patients and were generally categorized as mild and occasionally categorized as moderate.23,48,49,52-56,58-61,63-65 Irrespective of dose and duration, penicillin V showed the lowest risk of any adverse event when compared with doxycycline (OR, 0.42; 95% CI, 0.16-1.10; 14 studies, 9 agents [nodes], 1793 patients, and very low certainty; Figure 3B and Table).23,48,52-56,58-61,63-65 An additional analysis examining dosages and durations of the various treatment modalities, including an extended treatment regimen of doxycycline, 200 mg/d for 20 to 21 days, also did not show significant differences in adverse outcomes when compared with doxycycline, 200 mg/d for 14 to 15 days, as the reference treatment (12 studies, 15 modalities [nodes], and 1624 patients; eFigure 2 in the Supplement; individual study data are given in eTable 3 in the Supplement).23,48,49,52,53,55,58-60,63-65
Any Skin-Related Adverse Event
The percentage of patients with skin-related adverse events, such as photosensitivity, photodermatitis, or urticaria, was 3% (95% CI, 2%-6%) of patients. Irrespective of dose and duration, compared with doxycycline, cefuroxime axetil showed a significantly lower risk of skin reaction (OR, 0.18; 95% CI, 0.07-0.52; 9 studies, 6 agents [nodes], and 1211 patients; Figure 3C).23,48,52,54-56,58,63,65 When different antibiotic treatment modalities were compared irrespective of dose and duration with doxycycline, 200 mg/d for 14 to 15 days, all antibiotics in the network showed a nonsignificant decreased risk of skin-related adverse events (7 studies, 8 modalities [nodes], and 1006 patients; eFigure 3 in the Supplement).48,49,52,55,58,63,65 A pairwise meta-analysis that was not connected to the NMA showed that when compared with doxycycline, 300 mg/d, 20 or 21 days, the risk of skin-related adverse events was significantly decreased with cefuroxime axetil, 1000 mg/d for 20 days (OR, 0.17; 95% CI, 0.06-0.51; 2 studies and 355 patients).54,56
Any Gastrointestinal Tract Adverse Event
Gastrointestinal tract adverse events, namely vomiting, diarrhea, and abdominal or gastric pain occurred in 14% (95% CI, 10%-20%) of patients. No significant differences were detected in a comparison of antibiotics irrespective of dose and duration, (8 studies, 6 agents [nodes], and 926 patients; Figure 4A).23,52,54-56,58,63,65 In an analysis comparing doxycycline, 200 mg/d for 14 to 15 days, with various dosages and treatment durations of other antibiotics, azithromycin, 500 mg/d for 5 days, showed the lowest risk of gastrointestinal tract adverse events (OR, 0.45; 95% CI, 0.20-1.01; 4 studies, 5 modalities [nodes], and 439 patients; eFigure 4 in the Supplement).52,58,63,65 Further direct comparisons that were not connected to the NMA did not reveal any differences between the effect estimates for any gastrointestinal adverse event (comparison I: azithromycin, 250 mg/d for 5 days, vs doxycycline, 200 mg/d for 10 days [OR, 4.85; 95% CI, 0.45-51.66; 1 study and 57 patients]55; comparison II: amoxicillin plus probenecid, 1500 mg/d for 21 days, vs doxycycline, 200 mg/d for 20 or 21 days [OR, 0.32; 95% CI, 0.01-8.01; 1 study and 75 patients]23; comparison III: cefuroxime axetil, 1000 mg/d for 20 days, vs doxycycline, 300 mg/d for 20-21 days [OR, 1.44; 95% CI, 0.48-4.30; 2 studies and 355 patients]).54,56
Any Hematologic Adverse Event
The percentage of patients with hematologic adverse events, such as thrombocytopenia, was 1% (95% CI, 0%-3%). An NMA conducted irrespective of dosage and duration showed no difference among the antibiotic agents (3 studies, 3 agents [nodes], and 437 patients; Figure 4B). There was also no difference for hematologic adverse outcome when different treatment modalities were considered within pairwise meta-analyses (comparison I: azithromycin, 500 mg/d for 5 days, vs doxycycline, 200 mg/d for 14-15 days [OR, 2.29; 95% CI, 0.09-57.91; 1 study and 82 patients]52; comparison II: cefuroxime axetil, 1000 mg/d for 20 days vs doxycycline, 300 mg/d for 20-21 days [OR, 0.95; 95% CI, 0.10-9.23; 2 studies and 355 patients]).54,56
Jarisch-Herxheimer–Like Reaction
Jarisch-Herxheimer–like reaction occurred in 15% (95% CI, 11%-20%) of patients. No differences were identified in the comparison of agents irrespective of dose and duration (7 studies, 7 agents [nodes], and 710 patients; Figure 4C).23,54,56,58,61,63,64 Additional analyses examining various antibiotic treatment strategies using doxycycline, 200 mg/d for 14 to 15 days, as the reference also did not reveal any significant differences (3 studies, 5 modalities [nodes], and 244 patients; eFigure 5 in the Supplement).58,63,64 Moreover, different direct comparisons that could not be included in the network because of missing connectivity also did not reveal any differences in risk of Jarisch-Herxheimer–like reactions (comparison I: cefuroxime axetil, 1000 mg/d for 20 days, vs doxycycline, 300 mg/d, 20-21 days, [OR, 2.03; 95% CI, 0.49-8.45; 2 studies and 355 patients]54,56; comparison II: penicillin V, 3.0-4.5 Mio IU/d for 20-21 days, vs minocycline, 200 mg/d for 21 days [OR, 0.86; 95% CI, 0.02-45.54; 1 study and 39 patients]61; comparison III: amoxicillin [1500 mg/d] in combination with probenecid [1500 mg/d for 21 days] vs doxycycline, 200 mg/d for 20-21 days, [OR, 2.56; 95% CI, 0.61-10.77; 1 study and 75 patients]).23
This NMA addressed treatment response and risk of treatment-related adverse events following treatment of EM in early cutaneous LB with various antibiotic agents and treatment regimens. The studies were conducted in the United States or in various European countries. Despite differences in the spectrum of pathogens that may be present in different regions and given the extended study period of more than 25 years, the results were generally consistent across the trials, suggesting good applicability of the evidence in countries with high risk of borreliosis.
When antibiotic agents were compared irrespective of dose and duration, pooled effect sizes revealed no differences in response to treatment among the interventions up to 2 months following treatment initiation nor at 12 or more months following treatment initiation. In addition, different antibiotic treatment modalities (including 10, 14-15, and 21 days of doxycycline administration) did not differently contribute to EM resolution or the reduction of associated symptoms. Overall, treatment failures were rare (<5%), and most participants enrolled in the examined studies had good clinical outcomes regardless of the antibiotic agent administered or treatment modality used. Treatment-related adverse outcomes occurred in approximately 35% of patients, but the majority of those events were mild. Overall, penicillin V, regardless of dosage and treatment duration, was the antibiotic with the lowest risk of any adverse event (the reduction in effect size compared with that for doxycycline was 58%). Photosensitivity was the most commonly reported skin-related adverse event, and this occurred only in patients who used doxycycline. However, the low or very low certainty of evidence precludes any further speculation. Additional analyses considering different dosage and duration treatment modalities, including an extended treatment regimen of doxycycline for 3 weeks compared with that for 2 weeks, did not show significant differences in drug-related adverse outcomes (eFigure 2 in the Supplement).
The overall certainty of evidence was generally low, occasionally very low, meaning that further research is likely to change the estimate of effects. The major issues were wide confidence intervals (imprecision), indirectness and study limitations (high risk of bias) due to inadequate randomization and the lack of blinding of patients, health care professionals who administered treatment, and outcome assessors. Poor reporting of the included studies made the interpretation of the evidence additionally challenging.
Overall, NMA provides a useful tool for comparing several competing interventions to develop evidence-based clinical guidelines. However, some challenges exist in network connectivity, consistency, and similarity of studies for the study design, settings, patients and (co)-interventions. Although statistical heterogeneity was low, studies differed particularly in baseline characteristics, including the duration of EM, the inclusion patients of with symptoms additional to EM, study settings, and follow-up times; the contribution of these differences to treatment outcomes was unknown. Another issue may be the potentially unclear validity of the clinical diagnosis of EM. We included studies that used a clinical diagnosis of EM for patient enrollment, and this was often described only as physician-documented EM; thus, we had to rely on the authors' reports. The same issue was true for concomitant symptoms of the disease. It may be difficult for patients and clinicians to differentiate drug-related adverse events from concomitant symptoms of the disease, such as joint pain, neck stiffness, headache, tiredness, or myalgia, resulting in treatment failures. In addition, patient data for treatment responders and failures were not always sufficiently reported and thus could not be categorized and are lacking in the present analysis. Therefore, the corresponding results on response to treatment could be overestimated or even underestimated. The lack of a placebo group prevented assessment of the efficacy of drug treatment when compared with the natural course of disease. Our review was therefore able to only summarize outcome data for comparative effectiveness of antibiotics (relative efficacy) when used for the treatment of EM.
Patients with neuroborreliosis and damage of the nervous system may need to be treated different from patients with early cutaneous LB. A former review from our group67 and a Cochrane review68 addressing these patient populations concluded that there is a lack of well conducted controlled published studies. Therefore, currently, it is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of neuroborreliosis or neurologic manifestations. However, the majority of patients included in the assessed trials showed good outcomes, with symptoms resolving by 12 months of treatment initiation regardless of the antibiotic used.
Comparison With Other Reviews or Guidelines
Numerous systematic reviews and guidelines addressing the management of EM exist.17,21,28,42,66,69,70 For example, a descriptive review from 1999 concluded that oral beta-lactam antibiotics and tetracyclines are most effective as first-line treatment of EM and should be administered for 10 to 21 days.21 By contrast, the International Lyme and Associated Diseases Society emphasized in 2014 that antibiotic treatment regimens of less than 20 days should not be offered to patients with EM because failure rates may be unacceptably high.28 Sanchez et al71 provided an update on the treatment of EM in 2016, reporting a sufficient treatment response with a 10-day course of doxycycline. A current guideline from the German Dermatological Society also recommends doxycycline, 200 mg/d for 10 days with a maximum of 14 days, for adolescents and adults, but stresses that the treatment response of the individual patient needs to be closely observed.69 The latest evidence review by the National Institute for Health and Care Excellence in 201870 reported a lack of head-to-head studies comparing doxycycline and amoxicillin. Overall, the guideline concluded that doxycycline should be first-line therapy in EM. The present systematic review is the first review to also consider the results of a recently published study by Eliassen et al65, which directly compares doxycycline and amoxicillin. Conducting an NMA based on the best currently available evidence allowed us to perform quantitative analyses of interventions compared directly in head-to-head studies and of interventions that have not been directly compared in studies. This methodological approach is pivotal to guideline development in the absence of adequate head-to-head comparator evidence.72 Nonetheless, an NMA is not a substitute for a well-conducted randomized clinical trial.
Treatment failures were rare regardless of antibiotic agent or treatment regimen used. There was no high-certainty evidence that extended treatment schemes with doxycycline enhanced therapeutic efficacy in patients with early cutaneous LB. Placebo-controlled studies are not in line with ethical standards; therefore, a comparison between antibiotic treatment and no antibiotic treatment was not feasible in this patient population. The reasons for the designations of low or very low certainty for the relative efficacy and safety in our NMA were imprecision, risk of bias, and indirectness. Rigorously conducted studies with adequate sample size are needed to identify possible smaller differences in comparative effectiveness and to rule out relevant drug-related safety issues.
Corresponding Author: Christine Schmucker, PhD, Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany (schmucker@cochrane.de).
Published Online: October 3, 2018. doi:10.1001/jamadermatol.2018.3186
Author Contributions: Dr Schmucker had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Torbahn, Hofmann, Freitag, Dersch, Fingerle, Meerpohl, Schmucker.
Acquisition, analysis, or interpretation of data: Torbahn, Hofmann, Rücker, Bischoff, Freitag, Dersch, Fingerle, Motschall, Schmucker.
Drafting of the manuscript: Torbahn, Schmucker.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Torbahn, Rücker, Schmucker.
Obtained funding: Torbahn, Hofmann.
Administrative, technical, or material support: Fingerle, Motschall.
Supervision: Hofmann, Rücker, Dersch, Fingerle, Meerpohl, Schmucker.
Funding/Support: This study was supported in part by funding from the German Dermatological Society and the German Paul-Ehrlich-Society to Drs Torbahn and Hofmann and from the German Society for Pediatric Infectious Diseases to Dr Torbahn.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contribution: Cornelius Lehane, MD, Department of Anesthesiology and Critical Care, University Heart Center Freiburg–Bad Krozingen, Medical Center–University of Freiburg, Freiburg, Germany, provided proofreading and editing of an earlier draft of the paper but received no financial compensation for this contribution.


text:
Dead NASA satellite crashes to Earth this weekend
A defunct NASA satellite is expected to re-enter Earth's atmosphere Sunday night (Jan. 8).
The US military predicts that the 5,400 pounds (2,450 kilograms) Soil Radiation Budget Satellite (ERBS) will crash back to its home planet around 6:40 p.m. EST (2340 GMT) Sunday, plus or minus 17 hours, NASA officials said.
"NASA expects most of the satellite to burn up as it travels through the atmosphere, but some components are expected to survive reentry," agency officials said. wrote in an update (opens in new tab) on Friday evening (January 6). "The risk of anyone on Earth being harmed is very low — about 1 in 9,400."
Related: Kessler syndrome and the space junk problem
ERBS, part of NASA's three-satellite Earth Radiation Budget Experiment mission, launched into low Earth orbit aboard the space shuttle Challenger in 1984.
ERBS used three scientific instruments to study how our planet absorbs and radiates solar energy. It was designed to run for only two years, but kept ticking until 2005, after which it became quite a nugget space junk. Since then, Drag has been gradually pulling the spacecraft down.
The ERBS death dive comes on the heels of another more dramatic space junk fall.
For example, in 2022, two Chinese Long March 5B rocket cores weighing about 23 tons (21 metric tons) fell uncontrollably back to Earth. These crashes occurred in July and November respectively, each time about a week after the missiles helped launch new modules to China's Tiangong Space Station.
The first stages of other orbital rockets are sent to controlled destruction just after launch or come down for safe landing and future reuse (in the case of SpaceX blowers). So having the Long March 5B Falls drawn criticism from large segments of the space community.
ERBS is of course a different case; it has been on the air for nearly four decades. Still, the coming spacecraft crash is a reminder that Earth's orbit is populated by a lot of space debris, posing an increasing threat as more and more satellites lift up.
Mike Wall is the author of "Outside (opens in new tab)(Grand Central Publishing, 2018; illustrated by Karl Tate), a book about the search for extraterrestrial life. Follow him on Twitter @michaeldwall (opens in new tab). follow us on twitter @Spacedotcom (opens in new tab) or on Facebook (opens in new tab).
#Dead #NASA #satellite #crashes #Earth #weekend
CNN Exclusive: Secretive process to select astronauts for NASA's next moon mission

redpajama_set_name: RedPajamaCommonCrawl


text:
Tsutsugo, Newman homer in Pirates 5-4 win over Cardinals
Updated: 11:41 PM EDT Aug 21, 2021
WTAE
Pirates vs. Cardinals
SOURCE: WTAE
ST. LOUIS (AP) - Yoshi Tsutsugo and Kevin Newman homered and Ke'Bryan Hayes added a two-run single, rallying the Pittsburgh Pirates to a 5-4 victory over the St. Louis Cardinals on Saturday night. Leadoff hitter Ben Gamel added three hits and a walk, and Jacob Stallings had two hits in the Pirates' 12-hit attack. Chasen Shreve (2-1) pitched to one batter in the sixth, striking out Matt Carpenter. David Bednar, the sixth Pirates hurler, gave up a leadoff single in the ninth, but got the next three batters to earn his first save.Genesis Cabrera (2-4) allowed three runs on four hits in the seventh to take the loss. Newman singled with one out. With two outs, Gamel singled and Hayes followed with a single, driving in both. He took second on the throw home. Bryan Reynolds was intentionally walked. Tsutsugo singled home Hayes, giving Pittsburgh a 5-3 lead. Reynolds was out at home trying to score on the play.Chad Kuhl, who was reinstated from the COVID-19 list Friday, allowed three singles to start the seventh. Tyler O'Neill's sacrifice fly scored a run before Kuhl struck out Molina and Lars Nootbaar to get out of the jam. Kuhl, who had started in 84 of his 86 previous MLB appearances, had not pitched since starting on July 29. St. Louis scored twice in the sixth to take a 3-2 lead. Yadier Molina hit a one-out RBI single and, with two outs, Edmundo Sosa added a a run-scoring double off reliever Nick Mears. Tsutsugo, a 29-year-old Japanese slugger who joined Pittsburgh on Aug. 16, hit his second home run in as many days when he smacked the first pitch of the fourth inning over the wall in center field, giving Pittsburgh a 2-1 lead. The Cardinals tied it 1-1 on a two-out double to right field by Paul Goldschmidt after Tommy Edman had walked in the third. Pittsburgh took a 1-0 lead on a leadoff home run by Newman in the third. St. Louis entered the day 3 1/2 games behind Cincinnati and San Diego in the race for the second NL wild-card spot.J.A. Happ was making his fourth start as a member of the Cardinals since he was acquired from the Twins. The 37-year-old Happ checked the Pirates on six hits and a walk with eight strikeouts over six innings. In his second start of the season, Dillon Peters pitched five innings, allowing three hits and one run. CARDINALS HALL OF FAMEThe Cardinals Hall of Fame grew by four players Saturday with the inductions of Bill White, Keith Hernandez, Tom Herr, and John Tudor. All except White, who did not attend, were recognized as part of the pregame ceremony. Tudor, Herr and Hernandez entered the field riding in convertibles.TRAINER'S ROOMPirates: RHP Sam Howard (right oblique strain) worked two scoreless innings (25 pitches/18 strikes) while making his second rehab appearance Friday night at Toledo with Triple-A Indianapolis. Cardinals: LHP Kwang Hyun Kim played his first-ever game at the minor league level by pitching in his first rehab game at Triple-A Memphis. He threw 34 pitches. Depending on his recovery from the outing, the Cardinals will choose between another rehab outing or coming back to the team. ... OF Dylan Carlson (right wrist sprain) has played catch on the field. He is expected to return for the Aug. 24 series opener against the Tigers.UP NEXTPirates: LHP Steven Brault (0-1, 1.84) will be making his fourth start of the season in the finale of this series. The 29-year-old Brault tossed 5 2/3 scoreless innings but had a no-decision in his last start, a 2-1 loss at Dodger Stadium on Monday nightCardinals: Adam Wainwright (11-7, 3.26) is set to face the Pirates for the third time this season, and for the second time at Busch Stadium. He has a career-best eight-game win streak against the Pirates (July 7, 2016-present). His last loss to the Pirates was on April 3, 2016, in an Opening Day defeat.___(Copyright 2021 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed without permission.)
ST. LOUIS (AP) - Yoshi Tsutsugo and Kevin Newman homered and Ke'Bryan Hayes added a two-run single, rallying the Pittsburgh Pirates to a 5-4 victory over the St. Louis Cardinals on Saturday night.
Leadoff hitter Ben Gamel added three hits and a walk, and Jacob Stallings had two hits in the Pirates' 12-hit attack.
Chasen Shreve (2-1) pitched to one batter in the sixth, striking out Matt Carpenter. David Bednar, the sixth Pirates hurler, gave up a leadoff single in the ninth, but got the next three batters to earn his first save.
Genesis Cabrera (2-4) allowed three runs on four hits in the seventh to take the loss. Newman singled with one out. With two outs, Gamel singled and Hayes followed with a single, driving in both. He took second on the throw home. Bryan Reynolds was intentionally walked. Tsutsugo singled home Hayes, giving Pittsburgh a 5-3 lead. Reynolds was out at home trying to score on the play.
Chad Kuhl, who was reinstated from the COVID-19 list Friday, allowed three singles to start the seventh. Tyler O'Neill's sacrifice fly scored a run before Kuhl struck out Molina and Lars Nootbaar to get out of the jam. Kuhl, who had started in 84 of his 86 previous MLB appearances, had not pitched since starting on July 29.
St. Louis scored twice in the sixth to take a 3-2 lead. Yadier Molina hit a one-out RBI single and, with two outs, Edmundo Sosa added a a run-scoring double off reliever Nick Mears.
Tsutsugo, a 29-year-old Japanese slugger who joined Pittsburgh on Aug. 16, hit his second home run in as many days when he smacked the first pitch of the fourth inning over the wall in center field, giving Pittsburgh a 2-1 lead.
The Cardinals tied it 1-1 on a two-out double to right field by Paul Goldschmidt after Tommy Edman had walked in the third.
Pittsburgh took a 1-0 lead on a leadoff home run by Newman in the third.
St. Louis entered the day 3 1/2 games behind Cincinnati and San Diego in the race for the second NL wild-card spot.
J.A. Happ was making his fourth start as a member of the Cardinals since he was acquired from the Twins. The 37-year-old Happ checked the Pirates on six hits and a walk with eight strikeouts over six innings.
In his second start of the season, Dillon Peters pitched five innings, allowing three hits and one run.
CARDINALS HALL OF FAME
The Cardinals Hall of Fame grew by four players Saturday with the inductions of Bill White, Keith Hernandez, Tom Herr, and John Tudor. All except White, who did not attend, were recognized as part of the pregame ceremony. Tudor, Herr and Hernandez entered the field riding in convertibles.
Pirates: RHP Sam Howard (right oblique strain) worked two scoreless innings (25 pitches/18 strikes) while making his second rehab appearance Friday night at Toledo with Triple-A Indianapolis.
Cardinals: LHP Kwang Hyun Kim played his first-ever game at the minor league level by pitching in his first rehab game at Triple-A Memphis. He threw 34 pitches. Depending on his recovery from the outing, the Cardinals will choose between another rehab outing or coming back to the team. ... OF Dylan Carlson (right wrist sprain) has played catch on the field. He is expected to return for the Aug. 24 series opener against the Tigers.
Pirates: LHP Steven Brault (0-1, 1.84) will be making his fourth start of the season in the finale of this series. The 29-year-old Brault tossed 5 2/3 scoreless innings but had a no-decision in his last start, a 2-1 loss at Dodger Stadium on Monday night
Cardinals: Adam Wainwright (11-7, 3.26) is set to face the Pirates for the third time this season, and for the second time at Busch Stadium. He has a career-best eight-game win streak against the Pirates (July 7, 2016-present). His last loss to the Pirates was on April 3, 2016, in an Opening Day defeat.
(Copyright 2021 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed without permission.)


Wow, where do I start? I was that typical kid who loved to fish, hunt, rodeo, and be outdoors. Our family did everything together. We made alot of great and lasting memories.
The memory that changed my life the most was a bad car wreck in September of 1991. That changed my life forever. I didn't know it at the time but the Lord had plans for each and everyone one of us. I did know that there was one and only one God. I also knew that John 3:16 changes lives. John 3:16 "for God so loved the world that he gave his one and only son, that whoever believes in him shall not perish but have eternal life."
That eventually led my wife, Jacqueline and my self to a crossroads in our lives. I had been fishing with a guide on Texoma for a few years. That couple asked if my wife and myself ever thought about moving to Texoma and working as a full time fishing guide. We looked at each other and just laughed. There was no way that we could move away from all of our family and the best paying jobs that we have every had. Oh; and did I mention that this move was over 430 miles away. It meant a move where we had no home, no family, and no guaranteed income.
At this point both Jacqueline and I sought God's answer and we began to pray. The Lord started opening doors that no man could open and closing doors that nobody could shut. Then a verse became very important; Jeremiah 29:11 "for I know the plans I have for you, "declares the Lord," plans to prosper you and not to harm you, plans to give you hope and a future."
Next came the decision to move to Lake Texoma. With one wife and three children we set off to North Central Texas. This trip became our first challenge; we meet with several trials along the way starting with a blown truck engine that was pulling the boat. Most would have turned tail and headed back to the life of comfort; but we choose to trust in the Lord. We learned early on that God is always in control of everything.
Today we are happy to say we have totally turned our lives over to God; our business, our finances and all the activities of daily living. Even in mistakes we realize that God helps us get corrected and back on track.
One of my favorite verses is Mark 1:17 "come follow me, Jesus said, "and I will make you fishers of men." God's instruction for us is to love one another and that's the foundation for my love of being a fishing guide. I get to fellowship with new found friends, loved ones and my family. sharing God's light while catching fish is just a bonus. The part I love the most is watching young and old reel in that first fish of the day. Their faces light up, their hearts open up and one great day unfolds.
I always remind myself that Jesus told several fish stories; but the big difference is all his stories were true.
Remember; Keep the Faith and know that the Lord our God loves everyone.
PS; if your searching for a local church please accept our invitation to join us at Victory Life in Sherman on North Travis Street.


Wanting a place to call home is a natural desire and a basic human right. However, the number of people affected by homelessness each year in England and Wales is considerable and growing.
Based on official government statistics, in autumn 2017 the total number of people were sleeping rough in England was 4,751.1 This represents an increase of 169% since 2010 and a 33% increase since 2015. In Wales, 345 people were found to be sleeping rough in autumn 2017, which marks a 44% increase since 2015.2 Last year, in total more than 5,000 people were estimated to have slept rough across England and Wales.
While there is recognition from the public that homelessness is going up, new research from YMCA has found that just one in four young people who are homeless (26%) believe the public care about youth homelessness.
When thinking about themselves and their personal situation, even fewer young people who are homeless believe the public are concerned. Less than one in five homeless young people (19%) believe the public care about their situation. This sense that very few care about their plight suggests young people feel enough is still not being done to support them to avoid and escape homelessness.
We want YMCA Sleep Easy to be a way of showing young people who are homeless that the public do care about them and that they are trying to tackle the problem of homelessness by raising vital funds. If you would like more information on how you can support our national fundraising event it can be found on our dedicated Sleep Easy page.


text:
News Radar
Looking for press releases of a particular company? Enter company name (or keyword) here.
GeneQuine Biotherapeutics Closes Seed Financing with HTGF and Innovationsstarter Fonds Hamburg
Hamburg / Bonn - 12.11.2012
GeneQuine Biotherapeutics Closes Seed Financing with High-Tech Gründerfonds and Innovationsstarter Fonds Hamburg
The Hamburg, Germany-based biotech startup GeneQuine Biotherapeutics today announced the completion of a seven-figure seed financing round. Investors are the German seed funds High-Tech Gründerfonds, Bonn and Innovationsstarter Fonds Hamburg. Funding will be used to perform proof-of-concept studies with the lead product – a gene therapy drug for the treatment of osteoarthritis in horses.
GeneQuine Biotherapeutics develops gene therapy for the treatment of osteoarthritis, a degenerative joint disease with high unmet medical need. While osteoarthritis is the most common joint disorder in humans – especially in the aged population – it is also a major health problem with significant market volume in horses and dogs. GeneQuine initially targets the more easily accessible veterinary market with the lead product GQ-201 for osteoarthritis in horses and a second product candidate for dogs while the long-term goal is the development of a gene therapeutic drug for osteoarthritis in man.
The gene therapy technology for the treatment of osteoarthritis was co-developed by GeneQuine's co-founder Kilian Guse at Dr. Brendan Lee's research group at Baylor College of Medicine, Houston, USA and has already shown efficacy in an osteoarthritis mouse model. GeneQuine holds a worldwide, exclusive license for the technology and will use the raised funds to demonstrate proof-of-concept in a horse osteoarthritis model with the lead product GQ-201.
Kilian Guse, PhD, CEO and co-founder of GeneQuine, stated: "We are very happy to receive seed funding from the High-Tech-Gründerfonds and the Innovationsstarter Fonds Hamburg. With the funds and the support of our two investors we will drive the development of our lead product GQ-201 for osteoarthritis in horses and demonstrate proof-of-concept in the target species."
Also the High-Tech Gründerfonds is looking forward to the collaboration. Dr. Martin Pfister, investment manager, added: "The recent approval of the first gene therapy product for a rare disease in Europe will move the entire field forward. Financing the development of innovative therapies with strong proof-of-principle data is the core business of the High-Tech Gründerfonds. We are convinced that the company will be successful based on their know-how and the exciting market."
"The treatment of osteoarthritis constitutes one of the largest veterinary markets, however there is no product on the market to provide cure to the disease. The resulting unmet medical need was one of the key points for our investment decision. Furthermore we are happy to bring such a highly innovative company as GeneQuine to Hamburg", said Doreen Huhle, Investment manager at Innovationsstarter Hamburg.
About GeneQuine Biotherapeutics
GeneQuine Biotherapeutics is a Hamburg, Germany-based biotech startup company focused on the development of gene therapy for osteoarthritis. While initially targeting the relative easily accessible veterinary market, the long-term goal is to develop a gene therapeutic drug for osteoarthritis in humans. The gene therapy technology has shown efficacy in an osteoarthritis mouse model and the lead product GQ-201 for horses is now being tested in a proof-of-concept study in the target species.
For more information about GeneQuine Biotherapeutics visit: www.genequine.com
GeneQuine Biotherapeutics
Dr. Kilian Guse
Harburger Schlossstr. 6-12
phone: +49 40 766 29 28 5
info@genequine.com
About Innovationsstarter Fonds Hamburg
Innovationsstarter Fonds Hamburg invests venture capital in young and innovative start-ups based in Hamburg, in order to strengthen their research and development activities. Planned are equity investments up to 1 mio EUR in corporate entities. The assets under management have a volume of 12 Mio EUR and are equally provided by the Free and Hanseatic City of Hamburg as well as the European Fonds for Regional Development (EFRE). The management of the fonds is carried out by Innovationsstarter Hamburg GmbH, a fully-owned subsidiary of the Innovationstiftung Hamburg.
Doreen Huhle
Innovationsstarter Hamburg GmbH
Habichtstraße 41
phone: +49 40 6579805-9
huhle@innovationsstarter.co
www.innovationsstarter.com
About High-Tech Gründerfonds
High-Tech Gründerfonds invests in young, high potential high-tech start-ups. The seed financing provided is designed to enable start-ups to take an idea through prototyping and to market launch. Typically, High-Tech Gründerfonds invests EUR 500,000 in the seed stage, with the potential for up to a total of EUR 2 million per portfolio company in follow-on financing. Investors in this public/private partnership include the Federal Ministry of Economics and Technology, the KfW Banking Group, as well as fourteen industrial groups of ALTANA, BASF, B. Braun, Robert Bosch, CEWE Color, Daimler, Deutsche Post DHL, Deutsche Telekom, Evonik, Qiagen, RWE Innogy, SAP, Tengelmann and Carl Zeiss. High-Tech Gründerfonds has about EUR 565.5 million under management in two funds (EUR 272 million HTGF I, EUR 293.5 million HTGF II).
High-Tech Gründerfonds Management GmbH
Dr. Martin Pfister
Investmentmanager
Schlegelstraße 2
phone: +49 228 823 00 100
info@high-tech-gruenderfonds.de
www.high-tech-gruenderfonds.de
Publisher Contact Information:
Company profile of High-Tech Gründerfonds Management
Past press releases of High-Tech Gründerfonds Management.
Tech investments
From our Online Data Service
VC-backed companies
From our Radar
DATE AMOUNT SECTOR
Nov 25 €24.0M Internet commerce
Jan 10 €20.0M Business applications
Jan 10 €20.0M Biotechnology
Jan 10 €13.5M Artificial Intelligence
Jan 9 €4.0M Software development
Jan 9 N/A Internet services
Jan 9 €15.0M Business applications
For information on Europe's most extensive database on technology funding click here!
Identiq
identiq raises $5m seed, launches privacy-first identity validation...
Nethone
nethone raised over $1 million from innovation nest
The Link App
the link app launches version 2.0
Addex Therapeutics
addex sucessfully raises chf40 million in capital increase
urban jungle raises £1m in seed funding to build tech-enabled home ...
About us Contact us Legal Information
Emerging Technology Research Europe Inc. All rights reserved.


Surrounded by thousands of acres of private land, the South Fork lodge is perfectly situated to give you a unique and memorable getaway. Located just east of Coalville, Utah, the fresh, high mountain air will rejuvenate and relax you.
Our spacious, 6500-square foot lodge boasts 8 bedrooms, 7 bathrooms, and 8 additional sleeping cabins, each with 2 beds and a separate bathroom and shower facility. The large windows give you an unparalleled view of the outdoors, and the 20-foot tall fireplace gives you a comfortable space from which to enjoy that view. Our lodge also has a large wrap-around deck, flat screen TV, spacious kitchen, and a dining room that seats 26. It's hard to imagine a more perfect mountain ambiance.
If you think our amenities are great, wait until you hear about our activities! Our 70,000 acre property has an abundance of enjoyable activities for any season of the year. In the spring and summer, enjoy exploring the trails with hiking, mountain biking, horseback riding, and ATV tours. Anglers love our privately stocked fishing pond, as well as fly fishing in the Provo and Weber Rivers. Our archery and shooting ranges are also available to you, along with instruction and competition.
Winter activities are just as plentiful. Snow-filled options include cross-country skiing and snow-shoeing, dogsled and snowmobile tours, and horse-drawn sleigh rides. You can try your hand at ice-fishing, or take advantage of our transportation to 5 nearby world-class ski resorts.
The lodge is available for various lengths of stay. Contact us today for available dates!


There we were, hanging out in basements, listening to Weezer and eating snack foods covered in orange powder. If you were a little younger, maybe it was the Spice Girls and watching Titanic. But the great social equalizer of the late 1990s was Mario Kart 64. Whether you had your own console or your gaming was restricted to friends' houses, the game with the colourful go-karts and the bouncy music was a staple of the '90s adolescent experience.
For its latest fundraiser, Pink Triangle Services, Ottawa's queer community centre, has set out to recreate a little bit of that '90s magic. The centre offers a variety of support programs and meeting groups, and funds raised at the first annual Vintage Video Game Tournament will help with its operational costs.
Sixteen teams will compete in the tournament, with prizes awarded based on most funds raised, best team and solo cosplay, and to the tournament winner. A minimum pledge of $100 is needed for each team to be entered in the tournament, and participants are encouraged to seek sponsorship from friends and family members.
While each team can designate four players as "team drivers," there is no limit to the number of people who can be on a team, and solo players are also welcome. But unlike those times hanging out in friends' basements, there's more to do while you wait for your turn at the controller than just feeding Cheezies to the dog. "We have tabletop gaming provided by Monopolatte that you can rent out and just play some board games with your friends while you're waiting for your next turn," Michelle says.
Teams and individuals are also encouraged to come in costume as their favourite characters. "We figured, why not add another element where people could get a prize? . . . We want people to get really excited and involved and come dressed up," Michelle says. Prizes will be in basket form, containing items from a variety of local businesses. The idea is that each team member will have something to take away. "Unlike most of our fundraisers, the prizes will be all-ages appropriate, so there's no dildos." Local artists and designers will also have the opportunity to rent tables at the event to peddle their wares.
Artist Alley tables are still available; $40 for sellers and $25 for info-only.
To register a team, visit ptsottawa.org/events/vvgt.


These are a number of simple, do-it-yourself home improvement tasks, even if you're only a beginner. You can increase the value and improve the enjoyment of your home. Continue reading to learn some great tips for home improvement that are simple to do, and not hard to get started with.
A great way to save money on home upgrades is to comparison shop to find the best deals. Flooring of any type can cost a lot, especially if you're looking at hardwood or tile. It's always best to compare prices from a variety of different outlets. There's many discount stores that can help you save money.
You can easily dress up a teenager's room by creating pillows that serve as a trendy focal point. Go get some old clothes like a pair of jeans, some old concert t-shirts or anything with a cool design and fasten them around the pillows, then sew them on. This will help dress up your teen's room and add a splash of personality.
When tackling renovations in your bathroom or kitchen, don't forget to turn off the water to the room in which you are working before working on fixtures or plumbing. Sometimes homeowners forget about doing this and cause more problems for themselves.
A repainted garage door can add eye-catching appeal. Garage doors often get scratched or dinged, so a fresh coat of paint is a simple solution. Fresh paint does wonders for the look and value of your home. While you could paint the door a standard color, such as white, consider changing things up by choosing a contrasting color that compliments your home.
You don't need to live in a mansion to own a chandelier. You can get yourself an elegant chandelier for less than $500 to compliment any room. Total wattage of 200-400 adds extra sparkle and shine.
An excellent method of making your front lawn more attractive is to use outdoor accent lighting that is facing downward. This light can be nestled in trees to mimic dark, but natural, lighting. It may help emphasize lawn furniture or garden statues.
You can purchase standalone solar lighting in numerous styles; however, they are not usually very good for anything but decoration. The electric models are a better investment to add light and safety to paths and walkways. They cost more, but they are durable.
Prior to doing anything else, paint the room. Always paint the walls and ceiling prior to having new flooring installed. Regardless of whether or not you use protective coverings, it is almost impossible not to get at least a little paint on the floor.
As previously mentioned, a number of home improvement projects are easy enough for a novice to handle. Fixing things in your own home can be intimidating, yet rewarding. This article shared advice that should be instrumental in helping you get started.


text:
Back to Whimsical
Mercedes Lagunas
Garden of Light
$12.00 L4538-1P
9x12 image on 11x14 Paper - $12.00 USD 12x16 image on 13x19 Paper - $15.00 USD 15x20 image on 17x22 Paper - $24.00 USD 9x12 image on 13x16 Giclée - $30.00 USD 12x16 image on 16x20 Giclée - $36.00 USD 15x20 image on 19x24 Giclée - $54.00 USD
Image © Mercedes Lagunas
Mercedes Lagunas is a self-taught artist who discovered her love of art while studying Art History at University. Mercedes then embarked on a career as an airline stewardess for 10 years, which enabled her to see the world. Inspired by her travels, she was able to make the transition to her true passion: painting. Mercedes enjoys painting flowers and portraits most of all, and her vibrant images are filled with energy and joy. Besides painting, Mercedes has done illustration work for magazines, including The New Yorker. Her paintings are included in collections all over the world. She currently lives in Madrid, Spain, with her husband and son.
L4538-1P
Garden of Light Mercedes Lagunas


Former Cheetah Girl Adrienne Bailon was spotted in the streets of Soho in New York rocking a very trendy outfit mixed with denim and leather. She wore a leopard turban, denim shirt and a leather miniskirt with a Chanel belt, a $1640 Louis Vuitton Cruise 2012 Monogram Flore Chantilly Bag and $190 MICHAEL Michael Kors Fallyn Sandals. Just with the bag and shoes her outfit is over $1,830. LJ is here to save your wallets and help you get this outfit for a much lower price.
We are going to "ball on a budget" and get rid of name brands, so get a solid brown faux leather mini messenger bag. As for the top, denim shirts have been trending for a while now and can be found just about anywhere. Look for a washed denim blouse to match Adrienne's top. Tuck in the blouse to a camel mini leather skirt, the one I chose features accordion pleated detailing. Now back to accessories, her leopard print turban is what makes the outfit really unique. Get some matching caramel strap sandals, a thin braided or chain belt and rock some gold jewelery, and I bet your outfit will be way less than $1,000!


Cover Company´s Multi-Purpose Cleaner is a professional, solvent-free, multi-purpose cleaner designed to clean all exterior automotive surface materials quickly and safely. Highly effective on alloy wheel cleaning, grease, oil, exhaust soot and brake dust, it is also strong enough to strip most synthetic sealant coatings too (When CONC).
This is a multi-purpose cleaner that is unbeatable for rigorous cleaning of unloved wheel arches, engine bays and undercarriage areas. Avoid letting it dry out fully before it is rinsed off, otherwise stains may appear on treated surfaces. It´s is an excellent value for money intensive cleaning product, and one that we happily recommend to car care enthusiasts and professionals alike.
Interior - Spray onto a microfibre cloth and sparingly onto the area which is to be cleaned. If needed use a dry cloth to remove residue.
Exterior- Spray on to treated areas and agitage with a detailing brush, glove or alternative.