Contacting authors to retrieve individual patient data : study protocol for a randomized controlled trial

BACKGROUND: Individual patient data (IPD) meta-analysis is considered the "gold standard" for exploring the effectiveness of interventions in different subgroups of patients. However, obtaining IPD is time-consuming and contact with the researchers responsible for the original trials is usually required. To date, there are no studies evaluating different strategies to optimize the process for retrieval of IPD from such researchers. Our aim is to examine the impact of providing incentives to the researchers responsible for the trials eligible for a meta-analysis to submit their IPD. METHODS/DESIGN: We updated our previously published systematic reviews for type 1 diabetes mellitus comparing long- and intermediate-acting insulin regimens (from January 2013 to June 2015) and for Alzheimer's dementia comparing cognitive enhancers (from January 2015 to May 2015). Eligible were randomized controlled trials (RCTs) fulfilling the eligibility criteria of the systematic reviews. We will randomly allocate authors of the reports of these RCTs into an intervention or control group. Those allocated to the intervention group will be contacted by email, mail, and phone, and will be asked to provide the IPD from their RCT and will be given a financial incentive. Those allocated to the control group will be contacted by email, mail, and phone, but will not receive a financial incentive. Our primary outcome will be the proportion of authors who provide the IPD. The secondary outcomes will be the time to return the dataset (defined as the period between the information request and the authors' response with the dataset), and completeness of data. We will compare the response rates in the two groups using the odds ratio and the corresponding 95 % confidence interval. We will also use binary logistic regression and cox regression analyses to examine whether different RCT characteristics, such as study size and sponsor information, influence the probability of providing IPD and the time needed to share the data. DISCUSSION: This study will determine whether a financial incentive affects response rates when seeking IPD from the original researchers. We will disseminate our findings in an open access scientific journal and present results at national and international conferences. TRIAL REGISTRATION: This trial is registered in Clinical Trials.gov, ID number NCT02569411 . Date of registration 5 October 2015

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease

Venkata Raveendra Pothineni,1,* Mansi B Parekh,1,* Mustafeez Mujtaba Babar,1 Aditya Ambati,2 Peter Maguire,1 Mohammed Inayathullah,1 Kwang-Min Kim,1 Lobat Tayebi,3 Hari-Hara SK Potula,1 Jayakumar Rajadas1,4 1Biomaterials and Advanced Drug Delivery, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, School of Medicine, Stanford University, Palo Alto, CA, USA; 2Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Palo Alto, CA, USA; 3Department of Developmental Sciences, Marquette University School of Dentistry, Milwaukee, WI, USA; 4Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA *These authors contributed equally to this work Background: Lyme disease accounts for >90% of all vector-borne disease cases in the United States and affects ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%–20% of patients treated with current antibiotic therapy still show lingering symptoms.Methods: In order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). We have determined the MIC and MBC of four drugs for three Borrelia burgdorferi s.s strains namely CA8, JLB31 and NP40. The binding studies were performed using in silico analysis.Results: The MIC order of the four drugs tested is cefoxitin (1.25 µM/mL) > cefamandole (2.5 µM/mL), > cefuroxime (5 µM/mL) > cefapirin (10 µM/mL). Among the drugs that are tested in this study using in vivo C3H/HeN mouse model, cefoxitin effectively kills B. burgdorferi. The in silico analysis revealed that all four cephalosporins studied binds effectively to B. burgdorferi proteins, SecA subunit penicillin-binding protein (PBP) and Outer surface protein E (OspE).Conclusion: Based on the data obtained, cefoxitin has shown high efficacy killing B. burgdorferi at concentration of 1.25 µM/mL. In addition to it, cefoxitin cleared B. burgdorferi infection in C3H/HeN mice model at 20 mg/kg. Keywords: Lyme disease, Borrelia burgdorferi, antimicrobials, penicillin-binding protein

Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

Venkata Raveendra Pothineni,1 Dhananjay Wagh,1 Mustafeez Mujtaba Babar,1 Mohammed Inayathullah,1 David Solow-Cordero,2 Kwang-Min Kim,1 Aneesh V Samineni,1 Mansi B Parekh,1 Lobat Tayebi,3 Jayakumar Rajadas1 1Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, 2Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, 3Department of Developmental Sciences, Marquette University School of Dentistry, Milwaukee, WI, USA Abstract: Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved) that were screened are Library of Pharmacologically Active Compounds (LOPAC1280), the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150 unique compounds, which inhibited >90% of B. ­burgdorferi growth at a concentration of <25 µM. These 150 unique compounds comprise many safe antibiotics, chemical compounds, and also small molecules from plant sources. Of the 150 unique compounds, 101 compounds are FDA approved. We selected the top 20 FDA-approved molecules based on safety and potency and studied their minimum inhibitory concentration and minimum bactericidal concentration. The promising safe FDA-approved candidates that show low minimum inhibitory concentration and minimum bactericidal concentration values can be chosen as lead molecules for further advanced studies. Keywords: Lyme disease, Borrelia burgdorferi, BacTiter-Glo assay, high-throughput screening, persister