Search

Background.: This study estimates the maximum price at which mesenchymal stem cell (MSC) therapy is deemed cost-effective for septic shock patients and identifies parameters that are most important in making treatment decisions., Methods: We developed a probabilistic Markov model according to the sepsis care trajectory to simulate costs and quality-adjusted life years (QALYs) of septic shock patients receiving either MSC therapy or usual care over their lifetime. We calculated the therapeutic headroom by multiplying the gains attributable to MSCs with willingness-to-pay (WTP) threshold and derived the maximum reimbursable price (MRP) from the expected net monetary benefit and savings attributable to MSCs. We performed scenario analyses to assess the impact of changes to assumptions on the study findings. A value of information analysis is performed to identify parameters with greatest impact on the uncertainty around the cost-effectiveness of MSC therapy., Results: At a WTP threshold of $50,000 per QALY, the therapeutic headroom and MRP of MSC therapy were $20,941 and $16,748, respectively; these estimates increased with the larger WTP values and the greater impact of MSCs on in-hospital mortality and hospital discharge rates. The parameters with greatest information value were MSC's impact on in-hospital mortality and the baseline septic shock in-hospital mortality., Conclusion: At a common WTP of $50,000/QALY, MSC therapy is deemed to be economically attractive if its unit cost does not exceed $16,748. This ceiling price can be increased to $101,450 if the therapy significantly reduces both in-hospital mortality and increases hospital discharge rates.

Objective: A previous Trinidadian survey highlighted the investigative and therapeutic approaches selected by general practitioners (GPs) in managing thyrotoxicosis. The main objective of this study was to compare practice with existing guidelines. Methods: In this cross-sectional study a pretested de novo questionnaire was self-administered to GPs throughout Trinidad. The survey evaluated GPs' choices in management of thyrotoxicosis cases and compared their responses to the 2016 American Thyroid Association guidelines as well as with those previously reported locally. Results: A total of 159 completed questionnaires were analyzed (59% response rate). Thyroid stimulating hormone was the preferred (94%) biochemical test to confirm thyrotoxicosis etiology. A combination of ultra-sound and thyroid scintigraphy, thyroid ultrasound alone, and scintigraphy only were the testing options selected by 41%, 38%, and 12%, respectively. Generally medical therapy with antithyroid drugs was the preferred treatment option with 86% of respondents selecting this option for the index case of newly diagnosed female Graves disease. The greatest proportion of respondents that selected radioactive iodine (RAI) was 35% for both the index case as well as the male equivalent. Surgery was the most popular option at 25% for patients with a toxic multinodular goiter. Having access to RAI and scintigraphy was reported by 32% and 28%, respectively. Conclusion: GPs appear to be constrained to making rational choices based upon availability rather than what the guidelines recommend. In the absence of formal continuing medical education for GPs on thyrotoxicosis, dissemination of guidelines at the primary care level may reduce this gap. Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drugs; CME = continued medical education; GP = general practitioner; RAI = radioactive iodine; SURG = surgery; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Background: Women who have had preeclampsia (PE) are at increased risk for premature cardiovascular disease (CVD). The underlying pathophysiology of this risk remains unclear, but potentially involves subclinical vascular damage or dysfunction. Alterations in the levels of circulating microRNAs may be implicated, as they are known to play pervasive roles in vascular biology. We investigated whether levels of circulating microRNAs are altered between women with premature acute coronary syndrome (ACS), with and without a history of PE., Methods: Women with premature ACS (age ≤ 55 years) were categorized based on a prior history of PE or normotensive pregnancy. Relative plasma levels of 372 microRNAs were initially assessed by polymerase chain reaction array in a subset of subjects (n = 12-13/group) matched for age, chronic hypertension, dyslipidemia, and smoking status. Candidate microRNAs were then validated in a larger cohort of ACS patients (n = 176)., Results: MicroRNAs previously linked to angiogenesis (miR-126-3p), inflammation (miR-146a-5p), and cholesterol metabolism (miR-122-5p) were significantly decreased in women with prior PE compared to women with prior normotensive pregnancy (P = 0.002, 0.017, and 0.009, respectively), even after adjustment for chronic hypertension., Conclusions: Circulating levels of miR-126-3p, -146a-5p, and -122-5p were significantly decreased in women with premature ACS who reported prior PE compared to those with prior normotensive pregnancy. These data provide novel insight into potential pathways that may contribute to the increased risk of CVD following PE.

The U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research is responsible for evaluating drug safety and efficacy, including oversight of clinical trials and principal investigators. The FDA Clinical Investigator Inspection List (CIIL) contains online, detailed, relevant information of all FDA inspections. We reviewed FDA inspections of clinical investigators to ascertain their outcome and included all inspections on the list (July 1977 through December 31, 2009; n = 9,481 inspections). Eighty-eight percent of inspections were "data audit" (primary purpose = verification of data), and the rest (12%) were "for cause." The number of inspections each year significantly increased over time (P < 0.0001) and averaged 350 per year in the past decade. No deficiencies were found in only 11.2% of all "data audit" and 5% of all "for cause" inspections. Only 31% of inspections resulted in "no action indicated." About two thirds of inspections resulted in some finding, requiring either voluntary investigator action (61.3% of inspections) or official FDA action (3.9%). The most frequently cited deficiencies were failure to follow investigational plan (34%), inadequate informed consent form (28%), and inadequate/inaccurate records (27%). In conclusion, over the past decade, the FDA has performed approximately 350 inspections per year, with the number increasing over time. The vast majority of FDA inspections yield deficiency findings and, as a result, only about one third of inspections have an outcome of "no action indicated.", (©2014 American Association for Cancer Research.)

The quick, easy, cheap, effective, rugged, and safe (QuEChERS) and the U.S. Food and Drug Administration pesticide multiresidue methods were systematically tested for the analysis of aminocyclopyrachlor, a new synthetic auxin herbicide. Results revealed that these procedures are not suitable, highlighting the need for a publicly available residue method for this new active ingredient. Such a method has been developed and is reported herein for aminocyclopyrachlor residue analysis in vegetation, including white pine, Norway spruce, grass forage, and grass hay. Aminocyclopyrachlor residues were purified from plant tissue extracts by filtration through SPE cartridges with strong anion exchange stationary phases and analyzed using LC/MS/MS. This method was validated at five laboratories across the United States; their results were compared to evaluate reproducibility and ruggedness. The method LOQ was 0.01 mg/kg (ppm) and the LOD 0.003 mg/kg (ppm) for the matrixes tested. A qualitative procedure to confirm the molecular identity of residues based on retention time measurements and ion transition peak area ratios (m/z 214 --> 681m/z 214 --> 101) is also presented.

Cancer is the leading cause of death in Americans younger than 85 years of age and kills one American every 56 seconds. Advances in understanding of cancer biology have given us the potential to develop new, effective targeted therapies. However, progress is slowed by suboptimal/outdated clinical trial design paradigms and by regulatory complexity and rigidity. For instance, simulations suggest that restricting randomized trials to patients expressing drug target, instead of using unselected patient populations, could substantially reduce patient numbers required to demonstrate efficacy. High response rates that are achievable when patients and drugs are matched on the basis of molecular profiles may also make some randomized trials unnecessary or unjustifiable. Moreover, increasing the regulatory rigidity of clinical trials (regulatory fundamentalism) augments trial complexity and costs while slowing progress without demonstrating meaningful safety benefits. Time from drug discovery to marketing increased from 8 years in 1960 to 12 to 15 years currently. Toxic death rates on phase I trials have decreased from 0.8% in 1979 to 0.5% by 2002, but the estimated cost per life-year gained by tighter regulations is $2,700,000 (far higher than costs of other health measures), and simulations suggest that regulatory delays in development of effective therapies result in tens to hundreds of thousands of life-years lost, whereas stringent regulations save extremely few. Dysregulation is also a major disincentive to patient and clinician participation in clinical research. In summary, current approaches squander research resources and discourage research participation, and the marked imbalance between potential life-years lost versus saved renders the regulatory burden potentially unethical. We outline suggested solutions.

Purpose: To approve a new anticancer drug, the US Food and Drug Administration often requires randomized trials. However, several oncology drugs have been approved on the basis of objective end points without a randomized trial. We reviewed the long-term safety and efficacy of such agents., Methods: We searched the Web site of the US Food and Drug Administration's Center for Drug Evaluation and Research and MEDLINE for initial applications of investigational anticancer drugs from 1973 through 2006., Results: Overall, 68 oncology drugs, excluding hormone therapy and supportive care, were approved, including 31 without a randomized trial. For these 31 drugs, a median of two clinical trials (range, one to seven) and 79 patients (range, 40 to 413) were used per approval. Objective response was the most common end point used for approval; median response rate was 33% (range, 11% to 90%). Thirty drugs are still fully approved. United States marketing authorization for one drug, gefitinib (an epidermal growth factor receptor [EGFR] inhibitor), was rescinded after a randomized trial showed no survival improvement; however, this trial was performed in unselected patients, and it was subsequently demonstrated that patients with EGFR mutation are more likely to respond. Nineteen of the 31 drugs have additional uses (per National Comprehensive Cancer Network or National Cancer Institute Physician Data Query guidelines), and subsequent formal US Food and Drug Administration approvals were obtained for 11 of these (range, one to 18 new indications). No drug has demonstrated safety concerns., Conclusion: Nonrandomized clinical trials with definitive end points can yield US Food and Drug Administration approvals, and these drugs have a reassuring record of long-term safety and efficacy.

Objective: The purpose of this study was to determine if the food exchange system allows subjects' nutrient intake to remain at recommended levels during a weight-loss program., Design: Subjects in an intervention were prescribed an energy-restriction diet and exercise program lasting 32 weeks, and nutrient intake was measured prestudy and after 12, 16, and 32 weeks., Subjects/setting: Healthy but overweight and obese premenopausal women (n = 219) were recruited at 6 university sites into community-based weight loss programs. One hundred fifteen women completed all aspects of the study., Intervention: Energy intake was set at 0.8 x resting metabolic rate (RMR) for weeks 1 through 12, 1.0 x RMR for weeks 13 through 20, and 1.2 x RMR for weeks 21 through 32. Energy intake was based on food exchange tables, with the number of food exchanges adjusted to encourage a distribution of 55% carbohydrate, 30% fat, and 15% protein. Subjects increased their daily walking distance to 3.2 km above prestudy levels., Main Outcome Measures: Nutrient intake was measured from four 3-day food records., Statistical Analyses Performed: Repeated measures analysis of variance, with specific time point changes assessed from paired t tests adjusted for multiple comparisons., Results: Body mass decreased by a mean +/- SD of 6.7 +/- 3.2 kg at week 12 and 7.8 +/- 6.2 kg by week 32. Walking distance increased by an average of 17.2 +/- 10.0 km/week during the first 12 weeks, and 12.4 +/- 12.4 km/week during the last 20 weeks. Despite a 23% to 36% reduction in energy intake during the study, intake of most nutrients was maintained. Intake of vitamin E, calcium, iron, and zinc decreased significantly from prestudy levels during the first 16 weeks of the intervention, but not at week 32., Applications/conclusions: Intake of most nutrients can remain at recommended levels when overweight and obese women follow the American Diabetes Association/American Dietetic Association food exchange system during a community-based weight-loss program.