After hearing and assimilating this program, the listener will be better able to: ( 1 ) Increase his/her basic knowledge of important advances in medicine; ( 2 ) Identify a broad range of clinical research reported in the medical literature; ( 3 ) Synthesize research findings through one-on-one interviews with authors and editorialists; ( 4 ) Integrate new treatments reviewed in the summaries into current practice; ( 5 ) Challenge oneself with thoughtful, clinically relevant questions. Disclosure In adherence to the ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Philip Greenland reported receiving grant funding from the National Heart, Lung, and Blood Institute. Dr. Laurent Brochard reported receiving grants and personal fees from Covidien and grants from Fisher Paykel, General Electric, and Maquet, all outside of the submitted work. The planning committee members reported that they had nothing to disclose. WHEN TO START ART? NO LONGER A QUESTION Guidelines in the United States ( https://aidsinfo.nih .gov /guidelines ) recommend starting antiretroviral therapy in all patients who are positive for HIV, but there havent been any randomized trials supporting this approach in patients with high CD4-cell counts. Until now. In a study on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1506816 ), known by the acronym START, researchers randomized 4700 adults with CD4 counts higher than 500 cells/mm 3 either to start antiretroviral therapy immediately or to defer therapy until counts fell to 350 cells/mm 3 or lower. Based on an interim review released in Mayof this year ( www.jwatch.org /na38052 ), the trial was stopped early; we now have the full results. The median baseline CD4 count was 650 cells/mm 3 . In the deferred group, the median CD4 count at the start of antiretroviral therapy was 400 cells/mm 3 . The patients were followed for an average of 3years. The main findings are: The incidence of the primary composite endpoint namely, any serious AIDS-related event, any serious nonAIDS-related adverse event, or death was 60% lower in the immediate-antiretroviral therapy group than in the deferred group. In both of the groups, most of the adverse events were seen when CD4 counts were higher than 500 cells/mm 3 . Immediate antiretroviral therapy lowered the incidence of both AIDS-related and nonAIDS-related adverse events. Tuberculosis, Kaposi sarcoma, and lymphoma which are the most common AIDS-related events were all less common in the immediate therapy group. Cancer rates were lower in the immediate therapy group, but the prevalence of cardiovascular disease was similar in the two groups. If (as expected) the World Health Organization recommends antiretroviral therapy for all, the gap between the number of patients who get treatment worldwide (15 million) and the number needing therapy (almost 40 million) will grow. The START trial represents the closing of one chapter antiretroviral therapy is indicated for all, but it continues the challenge put to clinicians years ago : Diagnose, engage, and treat all people living with HIV. ACC/AHA GUIDELINES PREDICT CARDIAC RISK MORE ACCURATELY THAN ATP-III GUIDELINES The guidelines issued by the American College of Cardiology and the American Heart Association in 2013 on statin use to prevent atherosclerotic cardiovascular disease have been criticized for overestimating risk, especially in older patients ( www.jwatch.org /na37408 ). To determine the accuracy of the guidelines, researchers used data from the Framingham Heart Study to identify the risk for incident atherosclerotic cardiovascular disease in patients eligible for statin therapy according to those guidelines vs . the patients eligible under the Third Adult Treatment Panel guidelines from 2004. Details appear in the July14 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.7515 ). The study involved 2400 statin-naive patients with an average age of 51 and without known atherosclerotic cardiovascular disease; the patients underwent risk-factor assessment at baseline and were followed for a median of 9years. More patients were eligible for statin treatment under the American College of Cardiology and the American Heart Association guidelines than under the ATP-III guidelines (40% vs . 14%). During follow-up, there were 70 atherosclerotic cardiovascular disease events. Among the patients identified by the new guidelines as eligible for statin therapy, the rate of incident atherosclerotic cardiovascular disease was 6%; among the patients deemed to be noneligible for statin therapy, the rate was 1%. Among those classified as statin-eligible based on the ATP-III criteria, adverse cardiovascular events were seen in 7% of the patients; among those classified as noneligible, adverse events were seen in 2%. For those at intermediate risk according to Framingham criteria (a 10-year risk between 6% and 20%), the rate of atherosclerotic cardiovascular disease events was similar in the statin-eligible and the noneligible patients according to the ATP-III guidelines (at roughly 4%), but differed significantly between those classified as eligible or noneligible according to the American College of Cardiology and the American Heart Association (5% vs . 0.5%). The new guideline from the American College of Cardiology and the American Heart Association identifies a substantially larger proportion of the population as statin-eligible than does the Third Adult Treatment Panel guideline. This larger statin-eligible population includes more patients who are destined to have atherosclerotic cardiovascular disease events, but also many more patients who are not. Debate is likely to continue about what constitutes a reasonable number-needed-to-treat to prevent one adverse cardiac event in asymptomatic patients. LOW THRESHOLD FOR 10-YEAR RISK OF CVD MIGHT BE APPROPRIATE FOR STATIN TREATMENT The guidelines issued by the American College of Cardiology and the American Heart Association in 2013 recommend statin therapy for the primary prevention of atherosclerotic cardiovascular disease in four patient categories ( www.jwatch.org /NA32828 ). One of these categories is defined as patients with a 10-year risk for atherosclerotic cardiovascular disease of 7.5% or greater. Considerable criticism has been levied for what seems to be a low threshold (about half of all adults are eligible for statin treatment under this guideline), but a simulation study in the July14 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.6822 ) suggests that an even lower threshold could be cost-effective. Using well-known risk equations from the Framingham Heart Study, the modelers used national risk-factor databases; standard actuarial tables from the United States; data-based estimates of the incidence and the severity of statin adverse effects (including the risk for incident diabetes), adherence rates, and treatment effectiveness; healthcare and nonhealthcare costs (including drug costs); and measures of quality-adjusted life-years. In a hypothetical population of 1 million patients between the ages of 40 and 75 screened every 5years, outcomes and cost per quality-adjusted life-year were evaluated for various thresholds of a 10-year risk for atherosclerotic cardiovascular disease, from 1% to 30%. For example, at a risk threshold of 7.5% (which is the current recommendation of the American College of Cardiology and the American Heart Association), the cost was US$37,000 per quality-adjusted life-year, whereas at a risk threshold of 3% (resulting in two thirds of adults being eligible for treatment), the cost was $140,000 per quality-adjusted life-year, but 160,000 additional adverse cardiovascular events would be prevented. Like all simulation models, this one is sensitive to many assumptions, including drug cost, patient adherence, and the risk for developing diabetes. The researchers and editorialists note ( http:// dx.doi.org /10.1001/jama.2015.7434 ) that 10-year atherosclerotic cardiovascular disease risk thresholds lower than 7.5% are cost-effective based on accepted levels for cost per quality-adjusted life-year. But many clinicians would still be concerned about recommendations that would lead to two thirds of all adults being treated with statins, which would include essentially all older adults. LUNG ULTRASOUND OUTPERFORMS CHEST X-RAY FOR DIAGNOSING CHF Lung ultrasound can be used to diagnose congestive heart failure via the detection of B-lines (which are vertical hyperechoic lines extending from the pleural line to the bottom of the ultrasound screen that result from reverberation artifact owing to interstitial fluid in otherwise aerated lungs). In a multicenter study in the Julyissue of Chest ( http:// dx.doi.org /10.1378/ chest.14-2608 ), researchers in Italy evaluated the accuracy of lung ultrasound for detecting congestive heart failure in 1000 patients who presented with acute dyspnea. Ultrasound was performed in the emergency department by trained emergency doctors. Adjudication by two experts who relied on all available data (but were blinded to the lung ultrasound results) was the gold standard. A final diagnosis was acute decompensated heart failure in half of the patients. Negative and positive predictive values of the clinical evaluation plus lung ultrasound were both 97%. Lung ultrasound alone had negative and positive predictive values of 92%, which was significantly higher than the values of 76% for chest x-ray alone. In a subset of patients in whom brain-type natriuretic peptide was measured, lung ultrasound alone had higher negative and positive predictive values. Lung ultrasound could soon replace chest x-ray as the diagnostic modality of choice for pneumonia ( www.jwatch.org /na37878 ), and this study suggests that the same is true for congestive heart failure. Accuracy is operator-dependent, and robust training is needed, but this study suggests the technique is easily learned. PATIENTS WITH NEGATIVE EDEVALUATIONS FOR CHEST PAIN RARELY HAVE IN-HOSPITAL ADVERSECARDIACEVENTS Many patients who present with chest pain to emergency departments in the United States are admitted to observation or inpatient units for monitoring of potential adverse cardiac events and provocative testing. In a study in the Julyissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.1674 ), researchers reviewed medical records from three hospitals and quantified the risk for these adverse events namely, a composite of inpatient ST-segmentelevation myocardial infarction, serious arrhythmia, cardiac or respiratory arrest, and death in emergency department patients who presented with chest pain, pressure, tightening, and burning and who underwent serial negative troponin measurements (1 to 7hours apart). Of 11,000 patients, 0.2% had clinically relevant adverse cardiac events. Eighty percent of the patients with adverse events had abnormal vital signs, ischemic electrocardiogram findings, left bundle branch block, or pacemakers; the adverse events in the remaining patients were deemed to be potentially iatrogenic or noncardiac. Patients with negative emergency department evaluations for cardiac chest pain who have access to appropriate follow-up care should be discharged home. This study provides the necessary evidence to support patientdoctor decision making around this treatment plan. With such a low rate of adverse events, the findings show that clinicians might be doing more harm than good by admitting these patients for observation. OUTPATIENT TREATMENT LIKELY IS SAFE FOR PATIENTS WITH LOW-RISKVTE Most patients who get diagnoses of venous thromboembolism in emergency departments in the United States are admitted as inpatients to begin treatment, but this might not be necessary for patients at low risk. In an observational study in the Julyissue of Academic Emergency Medicine ( http:// dx.doi.org /10.1111/acem.12711 ), researchers at two academic emergency departments enrolled 100 low-risk patients with venous thromboembolism (two thirds with deep vein thrombosis, 30% with pulmonary embolism, and the rest with both), started them on rivaroxaban (trade name: Xarelto), and evaluated them at two follow-up visits at a dedicated clinic (at 2 to 5weeks and at 3 to 6months later). Low-risk status was determined using the Hestia criteria. During follow-up, no patient experienced recurrent venous thromboembolism, had major or clinically relevant bleeding (as defined by the International Society of Thrombosis and Hemostasis), or died. This study adds to mounting evidence that, with the initiation of anticoagulants, low-risk patients with venous thromboembolism can be treated as outpatients. But doing so requires that patients have access to appropriate and timely follow-up care, which is currently a barrier for many patients who present to emergency departments. Plus, at least one large randomized controlled trial on the topic is under way, and its results should influence widespread adoption of this practice. IS THE WELLS SCORE USEFUL FOR DIAGNOSING DVT IN HOSPITALIZEDPATIENTS? The Wells score was developed to prevent unnecessary ultrasound imaging in outpatients with nonspecific signs and symptoms of deep vein thrombosis. Although the Wells score has been validated in outpatient settings, it might not be accurate in hospitalized patients. In a prospective study in the Julyissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.1687 ), researchers used Wells scores ( www. emed.ie/Haematology/Wells.php ) 1 point each for the presence of risk factors like active cancer, immobilization, recent major surgery, swelling of the entire leg, and swelling of the calf and 2 points subtracted for an alternative diagnosis to evaluate 1200 hospitalized patients who underwent lower-extremity ultrasound for suspected deep vein thrombosis. The patients were classified by Wells score as being at low (below 1 point), moderate (between 1 and 2 points), or high (3 or more points) risk for DVT. Among the patients in whom ultrasound showed proximal deep vein thrombosis, the incidence was 6% in those classified as low risk, 10% in those classified as moderate risk, and 16% in those classified as high risk. Among the patients identified as having distal deep vein thrombosis, the incidence was 7% in the low-risk group, 9% in the moderate-risk group, and 10% in the high-risk group. The relatively small differences in the incidences of deep vein thrombosis across risk groups for both proximal and distal DVT render Wells score risk stratification of inpatients clinically unhelpful. Statistical analysis showed the Wells score to be barely better than chance in predicting DVT, presumably because the higher prevalence of DVT risk factors among inpatients, compared with outpatients, dilutes any discrimination. The net result is that most inpatients with any signs or symptoms suggestive of deep vein thrombosis will be evaluated with ultrasound. OBESITY AND AF: DOES WEIGHT LOSSLESSEN SYMPTOMS? We know that theres an association between the high prevalence of atrial fibrillation and obesity, but how does obesity contribute to atrial fibrillation, and does weight loss lessen this risk? Two studies in the Journal of the American College of Cardiology one in humans and one in animals shed light on this issue. In the first study ( http:// dx.doi.org /10.1016/ j.jacc.2015.03.002 ), researchers in Australia evaluated 360 overweight or obese adults with atrial fibrillation (they had body-mass indices of 27kg/m 2 or higher); the patients were offered weight-management assistance. At 4years, 140 patients lost 10% or more of their body weight, 100 lost 3% to 9%, and 117 lost less than 3%. The burden of atrial fibrillation (as observed by ambulatory monitoring and symptom severity) decreased significantly more from baseline in the group that lost the most weight than in the other two groups. Arrhythmia-free survival was also highest in the most successful weight-loss group, even when the researchers adjusted for the use of rhythm-control strategies, like drugs or ablation. Weight fluctuation was associated with a higher arrhythmic risk in all three of the groups. In the second study ( http:// dx.doi.org /10.1016/ j. jacc.2015.04.058 ), obese sheep had higher atrial volumes and pressures, more heterogeneity in atrial voltage and conduction, and more fibrosis (as well as an infiltration of atrial tissue with fat) than their lean counterparts. All of these changes could predispose to the development of atrial fibrillation. These two studies provide more insight on the association between obesity and atrial fibrillation. Obesity seems to be associated with electrical and structural changes that increase the propensity for atrial fibrillation, and weight loss seems to lower that risk. These findings are just another reason to stem the rising tide of obesity and to counsel patients on maintaining normal body weight. MEDITERRANEAN DIET MIGHT IMPROVE COGNITIVE FUNCTION Oxidative stress and endothelial dysfunction might play a role in the development of dementia, and an antioxidant-rich diet could provide protection. In a clinical trial in the Julyissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.1668 ), researchers performed a post hoc analysis of a subset of patients in a large study from Spain ( www.jwatch.org /jw201303120000001 ) to evaluate the association between a Mediterranean diet and age-related cognitive decline. They tracked more than 300 patients with an average age of 67 and without known cardiovascular disease, but with high cardiovascular risk based on traditional risk factors. The patients had been randomized to eat a Mediterranean diet supplemented with either 4 or more tablespoons /day of olive oil or 30 g /day of nuts or to a control group that was advised to reduce the intake of dietary fat. Batteries of neurocognitive tests were performed at baseline and after a median follow up of 4years. In adjusted analyses, barely significant differences favored either version of the Mediterranean diet over the low-fat control diet for composite measures of memory and overall cognition. The Mediterranean diet patients exhibited small average improvements in several measures, and the controls exhibited slight deteriorations. These results on the effects of a Mediterranean diet on age-related cognitive decline are modest at best, but theyre still intriguing. We need more rigorous studies on the topic. LESS-THAN-GOAL ENTERAL NUTRITION IS OK FOR CRITICALLY ILL PATIENTS Whats the right amount of nutrition for a patient whos critically ill? In the past, its been shown that higher-rate enteral nutrition wasnt necessarily better than low-rate enteral feeds ( www. cma j. ca/content/170/2/197.long and http:// dx.doi.org /10.1001/jama.2008.826 ). With these results in mind, researchers in Saudi Arabia and Canada evaluated the potential benefit of permissive underfeeding (meaning, restricted nonprotein calories, but preserved protein intake) in 900 patients predominantly in medical intensive care units at seven tertiary medical centers. The patients average body-mass index was 29kg/m 2 . Details appear in the June18 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1502826 ). The patients were randomized to either permissive underfeeding or standard feeding. Patients who got high-dose vasopressors or parenteral nutrition were excluded. On average, the underfeeding patients got half of their calculated caloric requirements, and the standard-feeding patients got 70% of their goal (average daily intakes were 840 vs . 1300kcal). Mortality at 3months, ICU-free days, and ventilator-free days were all similar in the two groups. The underfeeding patients had lower glucose levels, needed less insulin, and exhibited a lower average daily fluid balance than the standard-feeding patients, but all other secondary outcomes were similar. This study, in conjunction with earlier trials, shows that achieving full caloric intake in patients who are critically ill doesnt afford any clear benefit. Although permissive underfeeding didnt lower mortality at 3months, its worth considering for patients in whom better glucose control and lower fluid intake have important clinical implications. TWO TRIALS SUPPORT HIGH-FLOW OXYGEN USE IN PATIENTS WITH HYPOXEMIC RESPIRATORY FAILURE The use of noninvasive positive pressure ventilation in patients with exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary edema is well established, but its value in treating patients with hypoxemic respiratory failure isnt clear. High-flow oxygen delivered by nasal cannula might be an alternative to noninvasive positive pressure ventilation in these patients. Researchers, predominantly in France, explored this question in two multicenter randomized trials. In the first study, the results of which appearin theJune4 New England Journal of Medicine ( http://dx.doi.org/10.1056/NEJMoa1503326 ), researchers randomized 300 patients with hypoxemic respiratory failure (more than 60% had community-acquired pneumonia; none with hypercarbia) to high-flow oxygen, standard oxygen delivery, or noninvasive positive pressure ventilation. Standardized criteria for intubation were used, including relatively conservative thresholds for pH (lower than 7.35) and oxygen saturation (less than 90% for more than 5minutes). The rates of intubation were similar in the three groups, but trended lower in the high-flowoxygen group. This group also had a significantly lower mortality at 3months, more ventilator-free days, and less respiratory discomfort. In the second study, the results of which appear in the June16 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.5213 ), researchers compared noninvasive positive pressure ventilation with high-flow oxygen in 830 patients with hypoxemia after cardiothoracic surgery; reintubation rates were similar (at around 14%), as was intensive care unit mortality (about 6%) with the two modalities. The criteria for intubation were slightly more liberal in this study. These results support the use of high-flow oxygen in a select population of patients with acute hypoxemic respiratory failure and postoperative hypoxemia. High-flow oxygen should be first-line therapy in these patients. Importantly, no patient in these studies had hypercarbia. Ventilatory support (meaning, noninvasive positive pressure ventilation) remains the best treatment in patients with hypercarbic respiratory failure due to chronic obstructive pulmonary disease. This distinction in gas exchange abnormality (hypoxemia vs . hypercarbia) is essential in treatment decision-making. SUCCESSFUL FECAL MICROBIOTA TRANSPLANTATION FOR ACTIVEULCERATIVE COLITIS Fecal microbiota transplantation is safe and effective for treating patients with recurrent Clostridium difficile infections and is currently being studied for its potential in treating patients with other gastrointestinal disorders. In a study in the Julyissue of Gastroenterology ( http:// dx.doi.org /10.1053/ j. gastro.2015.04.001 ), researchers randomized 70 patients with active ulcerative colitis to either 50mL of donor fecal microbiota or placebo (which was 50mL of water) via weekly enema for 6weeks. The primary outcome was remission at 7weeks (with a Mayo score of 2 or lower and an endoscopic Mayo score of 0). The results were: The rate of remission in the fecal microbiota transplantation group was 25% vs . 5% in the placebo group. Three quarters of the patients in remission after fecal microbiota transplantation had the same individual donor. Fecal microbiota transplantation was not associated with any change in quality-of-life measures. At a follow-up of a year, nearly 90% of the patients in remission after fecal microbiota transplantation were still in remission. This study provides strong evidence in favor of fecal microbiota transplantation for treating patients with acute, active ulcerative colitis. Presumably, the feces of the most effective donor will be carefully studied for their microbial composition and potential use in further transplant studies. ELECTIVE SURGERY vs . MEDICALTHERAPY IN ADVANCEDULCERATIVE COLITIS Usually, patients with severe ulcerative colitis are treated with aggressive medical therapy; colectomy is reserved for patients who dont respond to medical treatment. In a retrospective cohort study on the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-0960 ), researchers examined mortality in 8000 Medicare and Medicaid patients with advanced ulcerative colitis who got elective colectomy or medical therapy. Advanced ulcerative colitis was defined as hospitalization for ulcerative colitis, 2 or more prescriptions for corticosteroids within 3months, or the use of immunosuppressants. Treatment during the past 6months included corticosteroids in about half of the patients, thiopurines in about 15%, and infliximab in about 6%. Mortality was 30% lower in the surgery group than in the medical-treatment group. In a post hoc analysis, lower mortality with surgery was confined to patients 50 or older (mortality was 40% lower in this group). Two hundred patients who underwent colectomy on the same day that they met criteria for advanced ulcerative colitis had the largest benefit (60% lower mortality). When those patients were excluded from the analysis, the survival benefit associated with surgery was not statistically significant. Three studies now suggest that patients 50 or older with advanced ulcerative colitis might benefit from elective surgery vs . continued medical treatment. Clinicians can reasonably advise patients of this finding because the information might affect decision-making in the face of advanced disease. But this study is not a randomized, controlled trial, and the percentage of patients who got tumor-necrosis-factor inhibitors and thiopurines was low, suggesting that these patients, in general, did not receive medical care reflective of current best practice ( http:// dx.doi.org /10.7326/M15-1190 ). SUPINE-ONLY SUPRAESOPHAGEAL REFLUX CAN BE LESSENED BY RAISINGTHE HEAD OF THE BED Supraesophageal reflux disease is the retrograde flow of gastric contents into the laryngopharynx and upper aerodigestive tract. It can be associated with throat clearing, cough, asthma, postnasal drainage, sinusitis, laryngopharyngitis, and sleep disturbance. In a retrospective chart review in the May/Juneissue of The Journal of Allergy and Clinical Immunology: In Practice ( http:// dx.doi.org /10.1016/ j. jaip.2014.11.019 ), researchers at a tertiary allergy clinic in the United States evaluated 240 patients with throat clearing, cough, postnasal drip, or globus sensation who underwent overnight nasopharyngeal pH monitoring. Nasopharyngeal reflux was present in 113 patients; of these, about 60% had reflux only in the supine position, and the rest had reflux in both upright and supine positions. Among the patients with supine-only reflux, 13 underwent repeat monitoring after the head of the bed was elevated by 6 inches. Reflux decreased in 10 patients after head-of-bed elevation, with 8 patients exhibiting a complete resolution of their supine reflux. Symptom improvement wasnt reported, so whether decreases in measurable reflux led to fewer upper airway symptoms is unclear. The pathophysiology of supraesophageal reflux disease is not well defined, and no large randomized, controlled trials have been conducted to evaluate its prevalence or patients responses to pharmacological therapies (like proton-pump inhibitors) or to raising the head of the bed. This study is a chart review and only included 13 patients in the intervention group. Still, the results were fairly dramatic. Nasopharyngeal pH monitoring is not widely available, so patients with unexplained upper airway symptoms, like throat clearing and cough, might benefit from a trial of sleeping with the head of their bed elevated. This intervention is inexpensive and safe, and, in theory, could be more effective than proton-pumpinhibitor therapy because it lessens reflux of all gastric contents rather than just raising pH. PRETREATMENT TO PREVENT RADIOCONTRAST REACTIONS DURING CT PROCEDURES Low-osmolality contrast material can cause nonIgE-mediated allergic-type reactions in patients undergoing computed tomography procedures. The risk for these reactions is 0.6% in all patients and rises to 3.5% in those who have a history of reactions. Typically, patients with past reactions get 50mg of prednisone at 13hours, 7hours, and 1hour before the administration of intravenous low-osmolality contrast material and 50mg of diphenhydramine at the 1-hour mark. In a retrospective study in the Julyissue of AJR American Journal of Roentgenology ( http:// dx.doi.org /10.2214/AJR.14.13810 ), researchers determined the rate of breakthrough reactions among 1100 inpatients between the ages of 5 and 97 who were pretreated before undergoing contrast-enhanced CT. Sixty percent of the patients had experienced past allergic-type reactions to low-osmolality contrast material; the rest had other reasons for pretreatment, including asthma and allergic reactions to other substances. For the patients with past reactions during contrast-enhanced CT, the breakthrough reaction rate was 2%; there were no breakthrough reactions among the patients without past reactions who were pretreated for other reasons. The number needed to treat to prevent 1 reaction of any severity was 70, and the number needed to treat to prevent 1 severe reaction was 570. Among the patients with past reactions, younger patients and those with multiple risk factors (especially severe allergies to 2 or more substances, like drugs and foods) had higher breakthrough-reaction rates. This study of the rates of breakthrough reactions in inpatients at high risk who get premedicated before contrast-enhanced computed tomography procedures is limited by its retrospective design and its use of past studies to determine predicted reaction rates. The high number needed to treat to prevent severe reactions makes one wonder if pretreatment is worth using at all. But until we have further prospective studies, clinicians should continue to pretreat patients whove had past allergic-type reactions to radiocontrast, paying special attention to atopic patients with asthma, food allergies, and drug allergies. BENEFITS FROM ARTHROSCOPIC INTERVENTION FOR DEGENERATIVE KNEE ARTHRITIS ARE MINIMAL Often, arthroscopic knee surgery is performed in middle-aged and older patients with knee pain, despite the fact that abnormal knee findings on magnetic resonance imaging are common and not necessarily associated with knee symptoms in these patients. Plus, sham-controlled studies have shown that this intervention is not beneficial ( www.jwatch.org /na33060 ). Even so, at least 700,000 knee arthroscopies are performed in the United States every year, and the incidence of arthroscopies in this population is increasing. In a systematic review and meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h2747 ), researchers evaluated nine studies (including 1300 patients) to determine the benefits and risks associated with arthroscopic meniscectomy, debridement, or both compared with control interventions (like sham lavage, exercise, placebo, or medical treatment). Not all of the patients in these trials had radiographic osteoarthritis. Follow-up ranged from 3months to 2years. At 3 and 6months, the arthroscopy patients experienced a small, statistically significant beneficial effect on pain relief compared with those who got control interventions, but this difference is not considered to be clinically relevant. This pain benefit disappeared at later time points, and there was no improvement in self-reported physical function. Surgical intervention incurred risks, including deep vein thrombosis in 4 per 1000 procedures and other adverse events. This meta-analysis once again drives home the point that arthroscopic surgical intervention for knee pain in middle-aged and older patients should not be the first therapeutic option. Any benefit is small and short lived and is almost identical to the benefit obtained with an exercise program. This study supports the clinical practice of analgesia and physical therapy (or observation) for these patients, rather than initial surgical intervention ( http:// dx.doi.org /10.1136/bm j. h2983 ). TREATING PATIENTS WITH GIANTCELLARTERITIS IS COMPLICATED BY RELAPSES Often, patients with giant cell arteritis are treated successfully with steroids, but tapering steroids can be difficult. Plus, relapses are common in patients with giant cell arteritis, and no steroid-sparing secondary therapies are uniformly effective. In a multicenter longitudinal study in the July Journal of Rheumatology ( http:// dx.doi.org /10.3899/jrheum.141347 ), researchers evaluated the frequency and features of relapses in 130 patients with giant cell arteritis who were followed for a median of nearly 2years. The patients average age at diagnosis was 70 and 80% were women. All of the patients met modified 1990 American College of Rheumatology criteria for giant cell arteritis ( http:// dx.doi.org /10.1002/art.1780330810 ), which do not require temporal artery biopsy for diagnosis; in this study, biopsy was performed in 100 patients and was consistent with giant cell arteritis in 80%. Relapse was defined as either new disease activity after a period of remission or worsening disease activity. During follow-up, 44 patients had 60 relapses. The most common symptoms of giant cell arteritis at the time of relapse were polymyalgia rheumatica and headache; ischemic symptoms (namely, limb claudication, jaw or tongue claudication, and vision problems) were seen in 30% of the relapses. Three quarters of the relapses happened while the patients were still taking glucocorticoids (the median dose of prednisone at the time of relapse was 7.5 mg/ day); only 17% of the relapses happened after prednisone discontinuation. Of note, erythrocyte sedimentation rates and C-reactive protein levels were normal in eight relapses. At the time of relapse, other medications the patients were taking included methotrexate (13 relapses), tumor necrosis factor inhibitors (2 relapses), and mycophenolate mofetil (also 2relapses). This study highlights the difficulties associated with treating patients with giant cell arteritis. Patients frequently relapse, and relapse can happen even with normal inflammatory markers. Despite the success of steroids in treating patients with this disease, clinicians need new biomarkers to help identify relapses and newer therapies for treating patients who relapse. TREATMENT OPTIONS ARE LIMITEDFOR PATIENTS WITH PROGRESSIVE SYSTEMIC SCLEROSIS Unfortunately, theres no definitive treatment or disease-modifying therapy for progressive systemic sclerosis. The most important pharmacologic advance in treating patients with this disease is the use of angiotensin-convertingenzyme inhibitors, which profoundly affect renal survival: Before ACE inhibitors were introduced, patients with progressive systemic sclerosis and renal crisis often underwent bilateral nephrectomy. Skin and lung manifestations of progressive systemic sclerosis are managed with cyclophosphamide, methotrexate, mycophenolate mofetil, or other agents. Some patients achieve modest improvement with these regimens, but none is strikingly beneficial. In a retrospective case-control study in the June Annals of the Rheumatic Diseases ( http:// dx.doi.org /10.1136/annrheumdis-2013-204522 ), researchers examined the effectiveness of rituximab in 120 patients with progressive systemic sclerosis; half had been treated with rituximab and half hadnt (the patients were matched by modified Rodnan Skin Score https:// www. med.umich .edu /scleroderma/patients/classification.htm , forced vital capacity, duration of follow-up, disease duration and subtype, and the use of immunosuppressive therapy). At 6months, average Rodnan scores had decreased significantly more from baseline in the rituximab group than in the control group. In the patients with interstitial lung disease, the rituximab users showed no average change in forced vital capacity, whereas average forced vital capacity declined by 5% in the controls. In this observational study, rituximab seemed to have a favorable effect on both skin fibrosis and pulmonary function. Although this wasnt a controlled trial, its findings point toward an option for an illness with few therapeutic alternatives. More trials are needed to define the role of rituximab in progressive systemic sclerosis. TWO COMMON DRUGS PROMOTE REMYELINATION IN DEMYELINATINGDISEASE OF MICE In multiple sclerosis and other demyelinating diseases, autoimmune attacks lead to demyelination. Approved therapies for MS target this immune attack and prevent further demyelination. An alternative approach to treating demyelination would be to encourage remyelination. Oligodendrocytes in the central nervous system have the ability to promote remyelination, but, typically, in people (and in other mammals), remyelination by oligodendrocytes is not sufficient. In a multisite study in the June11 issue of Nature ( http:// dx.doi.org /10.1038/nature14335 ), researchers screened a library of 730 small-molecule drugs to identify any that might cause mouse oligodendrocyte-progenitor stem cells to turn into myelin-producing oligodendrocytes. Surprisingly, two common topically applied drugs the antifungal miconazole and the steroid clobetasol potently induced this process. Although other steroids shared the anti-inflammatory effects of clobetasol, none shared its potent induction of remyelination. In several different mouse models of demyelination, including one that clinically and pathologically resembles chronic progressive multiple sclerosis in people, these drugs dramatically enhanced remyelination. For example, in one mouse model, more than 70% of axons in treated mice were myelinated, compared with only 6% in untreated mice. In another model, nearly all of the treated mice regained function of their hind limbs, whereas no untreated mice did. Finally, the researchers showed that these two drugs also induced human oligodendrocyte progenitor cells to form myelin-producing oligodendrocytes. In mice, two drugs miconazole and clobetasol that are already approved by the Food and Drug Administration for use in people dramatically encouraged remyelination in various demyelinating conditions and seem to have similar effects in vitro with human cells. This study will encourage human trials of remyelinating therapy , including testing whether these two topical drugs are effective when administered systemically. NO BLADDER CANCER RISK WITH PIOGLITAZONE USE Its been suggested that theres an elevated risk for bladder cancer in patients who take pioglitazone. In the July21 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.7996 ), researchers present three studies in which pioglitazone use was evaluated in patients who developed bladder cancer (in two studies) and other cancers (in the third study). All of the studies were conducted at a large integrated healthcare system in California. In a cohort analysis of nearly 200,000 patients with diabetes (18% were treated with pioglitazone for a median of 3years), the unadjusted incidence of bladder cancer was similar in those who did and those did not use pioglitazone. In a case-control analysis that involved almost 500 patients with incident bladder cancer and the same number of matched controls, again, pioglitazone use was similar in those with bladder cancer and in those without it. Finally, to evaluate the risk for 10 other cancers (prostate, pancreatic, breast, and colon, to name a few) in patients taking pioglitazone vs . patients who werent, the researchers performed a cohort analysis of 240,000 patients with diabetes (16% were treated with pioglitazone). During an average follow-up of about 6years, the risks for prostate cancer and pancreatic cancer were significantly higher in pioglitazone users. The researchers note that the excess risk found for pancreatic cancer might be explained by pioglitazone treatment for the hyperglycemia that often precedes the discovery of pancreatic cancer. But the excess risk found for both prostate cancer and pancreatic cancer requires further study. The results for bladder cancer are more reassuring, although a small elevation in the risk for bladder cancer with pioglitazone use could not be entirely excluded ( http:// dx.doi.org /10.1001/jama.2015.8232 and http:// dx.doi.org /10.1001/jama.2015.7151 ).
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