Citations

ObjectiveTo develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).MethodsWe conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.ResultsThe guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.ConclusionThis RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Objective To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA). Methods We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. Results The guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. Conclusion This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Purpose Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials. Methods Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index). Results Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found. Conclusion The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS.

AbstractIntroductionThe objective of our study was to investigate cross‐sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI).MethodsMagnetic resonance imaging scans of individuals from a population‐based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging.ResultsAtrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57–5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45–1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96–2.34; P = .08) for no atrial fibrillation and any infarction.DiscussionParticipants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone.

OBJECT Nonpowder guns, defined as spring- or gas-powered BB or pellet guns, can be dangerous weapons that are often marketed to children. In recent decades, advances in compressed-gas technology have led to a significant increase in the power and muzzle velocity of these weapons. The risk of intracranial injury in children due to nonpowder weapons is poorly documented. METHODS A retrospective review was conducted at 3 institutions studying children 16 years or younger who had intracranial injuries secondary to nonpowder guns. RESULTS The authors reviewed 14 cases of intracranial injury in children from 3 institutions. Eleven (79%) of the 14 children were injured by BB guns, while 3 (21%) were injured by pellet guns. In 10 (71%) children, the injury was accidental. There was 1 recognized assault, but there were no suicide attempts; in the remaining 3 patients, the intention was indeterminate. There were no mortalities among the patients in this series. Ten (71%) of the children required operative intervention, and 6 (43%) were left with permanent neurological injuries, including epilepsy, cognitive deficits, hydrocephalus, diplopia, visual field cut, and blindness. CONCLUSIONS Nonpowder guns are weapons with the ability to penetrate a child’s skull and brain. Awareness should be raised among parents, children, and policy makers as to the risk posed by these weapons.

AbstractThe schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis. Intracellular cholesterol levels are greatly reduced in cells incubated with 3‐deoxyschweinfurthin B (3dSB), an analog of the natural product schweinfurthin B. Decreased cholesterol levels are due to decreased cholesterol synthesis and increased cholesterol efflux; both of these cellular actions can be influenced by liver X‐receptor (LXR) activation. The effects of 3dSB on ATP‐binding cassette transporter 1 levels and other LXR targets are similar to that of 25‐hydroxycholesterol, an LXR agonist. Unlike 25‐hydroxycholesterol, 3dSB does not act as a direct agonist for LXR α or β. These data suggest that cholesterol homeostasis plays a significant role in the growth inhibitory activity of the schweinfurthins and may elucidate a mechanism that can be targeted in human cancers such as GBM.