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NEJM Journal Watch

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Program Written Summary NEJM Journal Watch Volume 25, Issue 03 February 1, 2014 Digital Media $24.99 Audio CD $27.99 The following is a list of articles summarized on this issue of NEJM Journal Watch Audio General Medicine. Journal Watch Audio Program Info Accreditation Info Cultural & Linguistic Competency Resources FOR ATRIAL FIBRILLATION, NEW ORAL ANTICOAGULANTS ARE MORE EFFECTIVE AND SAFER THAN WARFARIN Three new oral anticoagulants the thrombin inhibitor dabigatran (trade name: Pradaxa) and the factor Xa inhibitors apixaban (trade name: Eliquis) and rivaroxaban (trade name: Xarelto) are approved for preventing stroke and systemic embolism in patients with atrial fibrillation. Edoxaban, which is also a factor Xa inhibitor, but not yet approved by the Food and Drug Administration, is noninferior to warfarin for these indications ( www. jwatch .org /na32803 ). In a meta-analysis on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6736(13)62343-0 ), researchers report on the four major clinical trials in which these newer anticoagulants were compared head to head with warfarin in 70,000 patients with atrial fibrillation and an average age of 72. Median follow-up was 2years to 4years. Compared with warfarin, the newer agents were associated with significantly fewer strokes and systemic embolism events (19% fewer, driven mainly by 50% fewer hemorrhagic strokes). The new anticoagulants and warfarin were similarly effective in preventing ischemic stroke and myocardial infarction. Among those who got the newer agents, intracranial hemorrhage was 50% less common, and all-cause mortality was 10% lower, but gastrointestinal bleeding was 25% more common. The new anticoagulants effects relative to warfarin were consistent across all major subgroups, including those at different levels of stroke risk (as measured by the CHADS 2 score). The new oral anticoagulants seem to offer clear advantages over warfarin in efficacy, safety, and convenience in patients who have atrial fibrillation, although some adverse effects might emerge with longer-term use. ATRIAL ECTOPY IS ASSOCIATED WITH INCIDENT ATRIAL FIBRILLATION It has been shown that premature atrial contractions can initiate atrial fibrillation and that these contractions are associated with incident atrial fibrillation. In a multicenter, prospective study in the December3, 2013 Annals of Internal Medicine ( http://annals .org / article.aspx ?articleid=1784287 ), researchers evaluated the contribution of these premature contractions to predicting the RISK for atrial fibrillation by investigating the premature atrial contraction count in nearly 1300 patients with an average age of 71 without atrial fibrillation. The patients underwent 24-hour Holter monitoring at baseline and were followed for incident atrial fibrillation with annual electrocardiograms and by hospital-discharge data. During a median follow-up of 13years, a quarter of the patients developed atrial fibrillation. The median hourly premature atrial contraction count at baseline was significantly higher among those with incident atrial fibrillation than among those who did not develop it (roughly 5 beats /hour vs . 2 beats /hour ); the adjusted hazard ratio for incident atrial fibrillation was 5 among those with the highest vs . the lowest frequency of hourly premature atrial contractions. Adding contraction frequency to the Framingham risk model significantly improved 10-year atrial fibrillation risk discrimination. This study showed an association between higher premature atrial contraction counts and incident atrial fibrillation. The finding adds to our understanding of atrial fibrillation, but it will not be clinically useful until clinicians develop interventions that use these contraction counts to safely and effectively lower the incidence of atrial fibrillation. MORE AMBULATORY ACTIVITY IMPROVES CV HEALTH IN PATIENTS AT HIGH RISK Higher levels of self-reported physical activity have been associated with a lower risk for cardiovascular morbidity and mortality. But there is no documentation for this association when physical activity is measured objectively. In a randomized pharmacotherapy trial, the results of which were published four years ago ( www. jwatch .org /jc201003140000003 ), 9000 patients, 50 or older, who were at high risk for diabetes and cardiovascular disease used pedometers to record their ambulatory activity for 7 consecutive days at the start of the study and again after a year on a lifestyle modification program. Now, on the website of The Lancet ( http:// dx.doi.org /10.1016/ s0140-6736(13)62061-9 ), researchers report on the association between ambulatory activity at baseline and after a year and the risk for adverse cardiovascular events (namely, cardiovascular-related mortality, nonfatal stroke, or myocardial infarction). During an average follow-up of 6years, cardiovascular risk was 10% lower for every increment of 2000 steps /day in baseline activity, and was 8% lower for every increase of 2000 steps /day between the baseline and the 1-year measurements. Similarly, every 2000 steps-per-day decrease was associated with an 8% increase in cardiovascular risk. These associations were statistically significant, independent of each other, and unaffected by age, sex, body-mass index, and other potential confounders. Walking 2000 steps is roughly equivalent to 20minutes of moderately paced walking. In the absence of data from randomized trials, this analysis strengthens the evidence that increasing physical activity improves cardiovascular health in patients at high risk for adverse cardiovascular events. DIURETICS AND STATINS ARE ASSOCIATED WITH NEW-ONSET DIABETES It has been suggested that using β-blockers, diuretics, or statins increases the risk for new-onset diabetes. In a reanalysis of the randomized, controlled navigator trial data ( www. jwatch .org /jc201003140000003 ), researchers asked whether using β-blockers, thiazide diuretics, statins, or calcium-channel blockers was associated with new-onset diabetes in more than 9000 patients with impaired glucose tolerance and cardiovascular risk factors. Findings appear on the website of the British Medical Journal ( http:// dx.doi.org /10.1136/bm j. f6745 ). During a median follow-up of 5years, β-blockers, thiazide diuretics, statins, and calcium-channel blockers were each started in about 20% of the patients who did not have any past exposure to these drugs. After adjusting for multiple variables, the risk for new-onset diabetes was significantly higher in the patients who started diuretics or statins than in the patients who were not treated with diuretics or statins. The number needed to harm for diuretics was 17 and for statins, the number was 12. The risk for new-onset diabetes did not change among the patients who started β-blockers or calcium-channel blockers. In this study, thiazide diuretics and statins were associated with an excess risk for new-onset diabetes in patients with impaired glucose tolerance and cardiovascular risk factors. β-blockers and calcium-channel blockers were not associated with an increased risk. The researchers recommend that glycemia be monitored when diuretics and statins are started in patients at high risk. Although confounding is possible given the studys design, other studies have linked the use of statins ( www. jwatch .org /jw201107190000002 ), diuretics, and β-blockers ( www. jwatch .org /jw200605300000002 ) with new-onset diabetes. Even so, the benefits of these drugs probably outweigh this risk in selected patients. REMARKABLY EFFECTIVE AND NONTOXIC TREATMENT OF TYPE 2 DIABETES IN MICE Adiponectin is a hormone (made in fat cells) that binds to two receptors, AdipoR1 and AdipoR2, in muscle and liver cells. Patients with type 2 diabetes, insulin resistance, and obesity have low levels of circulating adiponectin. In mice, raising circulating levels of adiponectin protects against insulin resistance and glucose intolerance. Adiponectin seems to have both antidiabetic and antiatherogenic properties. In hopes of developing an orally available treatment that would mimic the effects of adiponectin and be relatively easy to produce, researchers in Japan identified a small molecule AdipoR agonist that stimulates the two adiponectin receptors in the same way as adiponectin. Details appear in the November28, 2013 issue of Nature ( http:// dx.doi.org /10.1038/nature12656 ). The adipoR agonist produced effects similar to those of adiponectin. It also reduced inflammation and oxidative stress and increased the biogenesis of mitochondria. The adipoR agonist prevented the insulin resistance and glucose intolerance that typically develops in mice that are fed high-fat diets, ameliorated diabetes in an obese mouse model, and lengthened the shorter lifespan of mice with diabetes. At least in mice, an orally available small molecule offered safe and potent protection against insulin resistance, glucose intolerance, and type 2 diabetes that develops in normal mice that like many people have restricted exercise and high-fat diets. It also offered protection, including longer lifespan, in genetically obese mice. This study will surely generate interest in human use. β -BLOCKERS ARE BENEFICIAL AND SAFE IN PATIENTS WITH COPD It has been suggested that β-blockers are safe and beneficial, yet underused, in patients with chronic obstructive pulmonary disease. In a retrospective population-based cohort study on the website of the British Medical Journal ( http:// dx.doi.org /10.1136/bm j. f6650 ), researchers in the United Kingdom explored whether β-blockers were associated with longer survival in 1000 COPD patients with first myocardial infarctions. Median follow-up after MI was nearly 3years. About a quarter of the patients were taking β-blockers before their hospitalization for MI, 20% got β-blocker prescriptions during hospitalization, and the rest never got prescriptions for β-blockers. Most of the prescribed β-blockers were cardioselective; on average, the β-blockers were well tolerated. After adjusting for multiple factors, the patients who took β-blockers before their MIs and the patients who got prescriptions for β-blockers during their hospitalizations were significantly more likely to survive than were the patients who never got β-blockers. Historically, clinicians have avoided prescribing β-blockers for patients with chronic obstructive pulmonary disease because of a concern that these drugs might cause harm (for example, bronchospasm). The results of this study and others ( www. jwatch .org /jw201106090000007 ) show that β-blockers are beneficial and safe in these patients who often have an excess risk for myocardial infarction and cardiovascular-related death. But whether β-blockers (even cardioselective ones) have adverse effects when administered during severe exacerbations of COPD is not clear. ACUTE KIDNEY INJURY FROM CALCIUM-CHANNEL BLOCKERS EXACERBATED BY CLARITHROMYCIN Theoretically, many drugdrug interactions confer risk, but are clinically insignificant. Still, the inhibition of cytochrome P 450 enzyme 3A4 can cause serious problems. Enzyme 3A4 inhibition by clarithromycin can cause excessive plasma levels of calcium-channel blockers, which in turn can cause hypotensive episodes and acute kidney injury. In a population-based retrospective study in the December18, 2013 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2013.282426 ), researchers in Canada identified two separate cohorts of 100,000 patients with an average age of 76 for whom clarithromycin or azithromycin (which does not inhibit enzyme 3A4) had been newly prescribed; all of the patients were chronic users of calcium-channel blockers. During the month following antibiotic prescription, the risk for hospitalization for acute kidney injury was 0.4% in the clarithromycin group vs . 0.2% in the azithromycin group. Differences of similar relative magnitude were seen for hospitalization for hypotension and for all-cause mortality. The risk was greatest among the patients who were taking clarithromycin and nifedipine. Although 460 patients would have to be coprescribed a calcium-channel blocker and clarithromycin for 1 patient to be harmed, frequent coprescribing of this combination could result in unnecessary hospitalizations and complications and in excess mortality. Clinicians should heed existing warnings from the Food and Drug Administration about serious adverse events caused by this drug combination. TIMING OF DIALYSIS IN PATIENTSWITH ACUTE KIDNEY INJURY Does the early initiation of dialysis benefit patients with acute kidney injury? To find out, researchers at a tertiary center in India evaluated 200 patients with community-acquired acute kidney injury who presented with progressively worsening renal function. The most common causes were sepsis, acute gastroenteritis, malaria, drugs, and undifferentiated acute febrile illnesses. The patients were randomized to begin intermittent hemodialysis either when serum creatinine level exceeded 7 mg/ dL (unless there was a compelling indication for earlier dialysis) or when dialysis was needed to manage refractory hyperkalemia, volume overload, acidosis, or uremic nausea (this was the usual-care group). Findings appear in the December2013 American Journal of Kidney Diseases ( http:// dx.doi.org /10.1053/ j. ajkd.2013.06.012 ). Average serum creatinine levels at the start of dialysis were 7.4 mg/ dL in the early group and 10.6 mg/ dL in the usual-care group. in-hospital mortality was slightly (but not statistically significantly) higher in the early group; dialysis dependence at 3months was 5% in both of the groups. The proportions of patients who recovered without needing dialysis were 8% in the early group and 17% in the usual-care group. Among those who underwent dialysis, the average time to the recovery of renal function was significantly longer in the early group (7days vs . 5days). According to the researchers, this is the largest randomized trial in which the timing of dialysis was evaluated in patients with acute kidney injury. Although the unique study population (patients in India with community-acquired acute kidney injury) limits the trials generalizability, the findings suggest no advantage and possible harm from starting dialysis based on an arbitrary threshold value for serum creatinine. RENIN-ANGIOTENSIN BLOCKADE BENEFITS PREDIALYSIS PATIENTS We know that renin-angiotensin system blockade with an angiotensin-convertingenzyme inhibitor or an angiotensin-receptor blocker benefits patients with mild-to-moderate renal failure ( www. jwatch .org /jw200109280000001 ), but we do not know whether these drugs cause reduced glomerular filtration rate and hyperkalemia in stage 5 patients who are not yet receiving dialysis. In a prospective cohort study on the website of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2013.12700 ), researchers in Taiwan identified about 30,000 predialysis patients (their average age was 65; their creatinine level was greater than 6 mg/ dL; and their hematocrit was lower than 28%; all of the patients were getting erythropoiesis therapy); roughly half of the patients got ACE inhibitors or angiotensin-receptor blockers within 3months after their serum creatinine levels exceeded 6 mg/ dL. The patients were followed until the start of dialysis, death, or the end of the study (the median follow-up was 7months). In analyses that were adjusted for clinical, healthcare, and demographic factors, the incidence of dialysis was significantly lower in the patients who got blockade than in those who did not (70 per 100 patient-years vs . 75 per 100 patient-years). The composite endpoint of dialysis or death was similarly lower in the blockade group. Hospitalization for hyperkalemia was more common in the blockade group, but all-cause mortality was similar in the two groups. Usually, predialysis patients are managed in collaboration with nephrologists, but these results will help primary care clinicians to be more comfortable with continuing renin-angiotensin blockade as renal insufficiency progresses toward requisite dialysis. LOWERING BP IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA AND RESISTANT HYPERTENSION Often, patients with resistant hypertension (who need 3 or more antihypertensive medications for even partial blood pressure control) have obstructive sleep apnea. It has been suggested that the usual treatment for sleep apnea namely, continuous positive airway pressure lowers blood pressure in patients with resistant hypertension. In a multicenter study in the December11, 2013 issue of JAMA ( http://jama.jamanetwork .com / article.aspx ?articleid=1788459 ), researchers in Spain randomized 200 patients with resistant hypertension and obstructive sleep apnea (and an average apnea-hypopnea index of 40 events /hour ) to either continuous positive airway pressure or no treatment. (The patients average age was 56, and 70% were men.) At 3months, the continuous positive airway pressure patients, compared with the control patients, had significantly greater reductions from baseline in both 24-hour average blood pressure and 24-hour diastolic pressure (declines of 3mmHg more), but not in 24-hour systolic pressure. Plus, a higher proportion of the treatment patients showed nocturnal drops in blood pressure as well. These results are similar to those of a recent smaller study from Brazil ( www. jwatch .org /na32861 ). Patients with obstructive sleep apnea of this severity are almost certainly candidates for and will benefit from continuous positive airway pressure, regardless of the presence of hypertension. This study shows a small, but clinically important, additional benefit in lowering blood pressure in patients with resistant hypertension. ADVERSE DRUG EVENTS ARE COMMON JUST AFTER HOSPITALIZATION Often, discussions of adverse drug events in older patients focus on Beers-criteria medications that are considered to be potentially inappropriate for anyone in this age group; drugs with adverse central nervous system effects, nonsteroidal anti-inflammatory drugs, and several cardiovascular drugs dominate the Beers list ( www. americangeriatrics .org /health_care_professionals/clinical_practice/ clinical_guidelines_recommendations /2012 and http:// dx.doi.org /10.1111/ j. 1532-5415.2012.03923.x ). In a study in the November2013 Journal of the American Geriatrics Society ( http:// dx.doi.org /10.1111/jgs.12504 ), researchers specifically focused on the adverse drug events that happened during the 6weeks after hospital discharge in 1000 consecutive hospitalized patients 65 or older. All of the patients lived in the community (not in long-term care facilities). At least one adverse drug event was seen in 19% of the cases. A quarter of the adverse events were considered to be serious or life-threatening, and a third were considered to be preventable. The most common types of adverse drug events were gastrointestinal, renal-electrolyte, and cardiovascular; the most commonly implicated drug classes were cardiovascular drugs, diuretics, opioids, antithrombotic agents, and antibiotics. Only 17% of the implicated drugs carried a strong recommendation for avoidance on the Beers list. Do clinicians need yet another reminder about the hazards of drug prescribing in older patients? The answer is probably: This study highlights the vulnerable immediate posthospitalization period, when patients are exposed to newly prescribed drugs just following acute illness. Plus, these findings point out that just about any drug class (not just drugs on the Beers list) is potentially hazardous. IS METABOLICALLY HEALTHY OVERWEIGHT OR OBESITY A MYTH? For years, people have debated whether high body-mass index is itself an independent risk factor for adverse cardiovascular outcomes or whether these adverse outcomes are mediated by metabolic abnormalities that often accompany high body-mass index. In other words, are metabolically healthy overweight patients (with body-mass indices between 25kg/m 2 and 30kg/m 2 ) or obese patients (with body-mass indices of 30kg/m 2 or higher) at a greater risk for adverse outcomes than normal-weight patients? To address this question, researchers performed a systematic review and meta-analysis of 12 observational studies (with nearly 70,000 patients) in which metabolic status and cardiovascular outcomes were reported. Details appear in the December3, 2013 Annals of Internal Medicine ( http://annals .org / article.aspx ?articleid=1784291 ). The patients were classified as metabolically unhealthy if they exhibited components of the metabolic syndrome, namely, a large waist circumference, elevated triglycerides, a low HDL cholesterol level, hypertension, diabetes, or an elevated fasting glucose level. In the studies with at least 10years of follow-up, metabolically healthy overweight patients and metabolically healthy normal-weight patients had similar risks for all-cause mortality and adverse cardiovascular events, whereas metabolically healthy obese patients had an excess risk. Metabolically unhealthy normal-weight, overweight, and obese patients all had excess risks for all-cause mortality and adverse cardiovascular events, compared with healthy normal-weight patients. The researchers found that normal weight does not protect metabolically unhealthy patients and that even metabolically healthy obesity is associated with excess risks for all-cause mortality and adverse cardiovascular events. Interestingly, an excess risk was not seen in metabolically healthy patients who were overweight, but not obese (with body-mass indices between 25kg/m 2 and 30kg/m 2 ). THREE-YEAR RISKS AND BENEFITSOF BARIATRIC SURGERY About 5years ago, a longitudinal multisite study of bariatric surgery from the United States showed that perioperative complications were more common in 1700 patients who underwent laparoscopic or open Roux-en-Y gastric bypass than in 600 patients who underwent laparoscopic adjustable gastric banding ( www. jwatch .org /jw200907300000002 ). Now, in a study in the December11, 2013 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2013.280928 ), researchers report longer-term results of this study of patients with an average age of 46 and a baseline body-mass index of 46kg/m 2 . Most of the patients were women. At 3years after surgery, the average weight loss for the bypass patients was 30% of their baseline body weight, and for the banding patients, it was 16% of their baseline body weight; most of the weight loss happened during the first year. Roughly two thirds of the bypass patients who had diabetes at baseline had at least partial remission, compared with a quarter of the banding patients. The two groups experienced similar improvements in dyslipidemia. Mortality at 3years was low and similar in the two groups (at about 1%). Revision and reoperation rates were much higher in the banding than in the bypass group (18% vs . 0.3%). The short-term risks were greater with gastric bypass, and the long-term rates of revision and reoperation were higher with banding. Generally, the overall results at 3years are encouraging for both procedures, but we do not really know much about long-term clinical outcomes, quality of life, and psychosocial functioning. The implications of this substantial alteration in nutritional, metabolic, and gastrointestinal physiology are yet to be fully understood. WHICH Red Flags PORTEND RISK FOR SPINAL MALIGNANCY OR FRACTURE IN PATIENTS WITH LOW BACK PAIN? Which history and physical examination red flags are useful for identifying the patients with low back pain who are at an excess risk for spinal malignancy or fracture? To answer that question, researchers systematically reviewed 14 studies (9 related to malignancy, 8 related to fracture, and 3 related to both). Eight of the studies were from primary care, and six were from secondary or tertiary care. Findings appear on the website of the British Medical Journal ( http:// dx.doi.org /10.1136/bm j. f7095 ). The prevalence of malignancy and fracture varied according to the setting; the prevalence of malignancy ranged from 0.2% to 7%, and the prevalence of fracture ranged from 2% to 9%. More than 20 different red flags were evaluated to screen for malignancy, and 30 were evaluated to screen for fracture. For malignancy, a history of cancer had the highest post-test probability, whereas old age, unexplained weight loss, and the failure to improve after a month had low post-test probabilities. For fracture, the red flags with the highest post-test probabilities were the presence of a contusion or an abrasion, the prolonged use of corticosteroid drugs, trauma, and an age older than 64; the probability of fracture was higher when multiple red flags were present. According to this systematic review, only a handful of red flags are useful in identifying the patients with low back pain who are at an excess risk for spinal malignancy or fracture. Notably, some guidelines list a variety of redflags and recommend imaging for patients with any red flag . But that approach results in many unnecessary imaging studies. ANASTROZOLE AND THE PREVENTION OF BREAST CANCER The selective estrogen-receptor modulators tamoxifen and raloxifene (trade name: Evista) are the only agents approved for preventing breast cancer in women at high risk. In a study on the website of The Lancet ( http:// dx.doi.org /10.1016/S0140-6736(13)62292-8 ), researchers compared the efficacy and the safety of the aromatase inhibitor anastrozole vs . placebo in nearly 4000 postmenopausal women (with a median age of 60) who had an excess risk for breast cancer. During 5years of follow-up, the overall incidence of breast cancer was significantly lower in the anastrozole group than in the placebo group, but anastrozole did not significantly lower the incidence of receptor-negative invasive tumors. Overall mortality was 1% in both of the groups. Arthralgias, carpal tunnel syndrome, vasomotor symptoms, vaginal dryness, hypertension, and dry eyes were significantly more common with anastrozole. The rates of fractures and cardiovascular events were similar in the two groups. The reduction in the risk for breast cancer with anastrozole is similar to that seen for the aromatase inhibitor exemestane and greater than that reported for selective estrogen-receptor modulators. The American Society of Clinical Oncologists supports the off-label use of exemestane for chemoprophylaxis in women at high risk; the findings of the current study could lead the Food and Drug Administration to approve anastrozole for this indication. But an editorialist is skeptical ( http:// dx.doi.org /10.1016/S0140-6736(13)62555-6 ): He points out that the prevention of receptor-positive tumors might actually represent the early treatment of preexisting tumors and that the likelihood of an eventual breast cancer mortality benefit seems small . So in the absence of a clear mortality benefit, the toxicity associated with long-term estrogen deprivation raises questions about the value of this strategy. This study was partially manufacturer-funded. α -BLOCKERS vs . α -BLOCKERSPLUS ANTICHOLINERGICS FOR BENIGNPROSTATIC HYPERPLASIA In patients with benign prostatic hyperplasia, α-blockers, like tamsulosin and doxazosin, work primarily by relieving obstructive symptoms (for example, incomplete emptying and a weak stream). But many patients with benign prostatic hyperplasia also have storage symptoms (such as frequency, urgency, and nocturia) for which anticholinergic drugs, like oxybutynin and tolterodine, might be helpful. In a meta-analysis in the December2013 Journal of Urology ( http:// dx.doi.org /10.1016/ j. juro.2013.05.058 ), researchers reviewed 7 studies (including nearly 4000 patients) in which α-blocker monotherapy was compared with combination therapy (an α-blocker plus an anticholinergic agent). Combination therapy, compared with monotherapy, improved symptoms on a storage subscore of the widely used International Prostate Symptom Score ( www. urospec .com /uro/Forms/ipss.pdf ); although the difference was statistically significant, it averaged only 0.7 points on the 15-point subscore. One concern about add-on anticholinergic therapy is a predisposition to acute urinary retention; this was seen significantly more often with combination therapy than with monotherapy during 3months of treatment. The researchers suggest that their findings confirm the efficacy and safety of combination therapy with an α-blocker and an anticholinergic agent for benign prostatic hyperplasia. But some clinicians may disagree because the researchers only reported outcomes on the storage subscale of the International Prostate Symptom Score; findings of the three largest trials included in this analysis showed that add-on anticholinergic therapy did not improve total symptom scores (comprising both storage and obstructive symptoms) or quality-of-life scores. Plus, even 1 additional case of acute urinary retention per 100 treated patients is concerning in a 3-month study; what might happen over 1 or 2years? Finally, the researchers do not discuss the nonurinary side effects of anticholinergic drugs in older patients. Although combined therapy might be worthwhile for selected individuals, on average, the potential benefits do not outweigh the potential harms. STUDIES IN YEAST REVEAL POSSIBLE TREATMENT FOR PARKINSON DISEASE Yeast are single-celled organisms: They do not have brains, or even neurons, yet they have revealed a potential approach to neurodegenerative diseases ( www. jwatch .org /jw200607070000002 ). The protein α-synuclein has been implicated in promoting Parkinson disease. In two studies in the November22, 2013 issue of Science ( http:// dx.doi.org /10.1126/science.1245321 and http:// dx.doi.org /10.1126/science.1245296 ), researchers have shown that N -aryl benzimidazole protects against α-synucleininduced toxicity both in yeast and in worm neurons. To analyze this phenomenon in people, the researchers removed skin cells from patients who carry a mutation that greatly increases the production of α-synuclein and leads to parkinsonism. The team created induced pluripotent stem cells from the differentiated skin cells, which were the equivalent of each patients embryonic stem cells ( www. jwatch .org /jw200812290000014 ). Then, they induced these pluripotent stem cells to form adult neurons, genetically indistinguishable from the unaffected neurons in that patients brain. N -aryl benzimidazole protected against α-synucleininduced toxicity in these neurons, suggesting (but not proving) that N -aryl benzimidazole might prevent Parkinson disease in such genetically vulnerable people and might even be valuable in treating parkinsonism in the patients who develop it without such underlying genetic vulnerability. These studies show once again that the simple systems used by basic science biologists (like single-celled yeast) can reveal insights about diseases in people. They also show the power of the Nobel Prizewinning discovery of induced pluripotent stem cells: The ability to create, and study in a laboratory dish, a specific cell that is genetically identical to one inside the body of a human being. INCREASING USE OF PREOPERATIVE CONSULTATIONS AMONG MEDICARE PATIENTS UNDERGOING CATARACT SURGERY For patients undergoing elective surgery, surgeons or anesthesiologists sometimes request separate preoperative consultations. Although these consultations are reimbursed by Medicare, we are not really sure of their necessity or value. In a retrospective study on the website of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2013.13426 ), researchers used a Medicare database to evaluate preoperative consultation use in roughly 600,000 patients 66 or older who underwent first cataract surgeries between 1995 and 2006. Most of the consultations were provided by internists and family physicians. During the study period, the frequency of preoperative consultations significantly increased from 11% to 18%. Among the patients who underwent surgery in 2005 or 2006, those who got preoperative consultations, compared with those who did not, were more likely to be older, female, non-black, residing in urban areas, and living in the northeastern part of the United States; they were also more likely to have undergone cataract surgery in a hospital (inpatient or outpatient) rather than an office or ambulatory setting. The patients who got preoperative consultations had higher levels of comorbidities, but these differences were small. Consultation frequency varied substantially (from 0% to 70%) across 300 hospital referral regions. Although this retrospective study cannot tell us which preoperative consultations are medically appropriate, the geographic and other factors associated with higher rates of preoperative consultations suggest mostly nonmedical reasons for the researchers findings. Research and guidelines that clarify when preoperative consultations are likely to be useful would be helpful. SHOULD HYPERGLYCEMIA IN CRITICALLY ILL CHILDREN BE TIGHTLY CONTROLLED? Whether tight glycemic control improves outcomes in critically ill children is not clear. In a multicenter study in the January9, 2014 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1302564 ), researchers randomized 1400 children in 13 intensive care units either to tight glycemic control (administering intravenous insulin to maintain glucose levels between 72 mg/ dL and 126 mg/ dL) or to conventional glycemic control (administering IV insulin to maintain glucose levels lower than 216 mg/ dL). The children were younger than 16 and nearly two thirds were younger than 1. All of the patients were getting mechanical ventilation and vasoactive drugs following critical illness, injury, or major surgery; 60% had undergone cardiac surgery. At a month, there were no differences in the two groups in the number of days alive and free from mechanical ventilation or in the number of days in the ICU. Moderate and severe hypoglycemic episodes were more common with tight glycemic control than with conventional control. Among the cardiac-surgery patients, mortality at a year was higher in the patients with hypoglycemia than in the patients without it. Among the patients hospitalized for reasons other than cardiac surgery, mortality was similar in the two groups, and the average hospital stay was about 2weeks shorter and less costly in the tight-control group. These savings were not realized in the cardiac-surgery group. These results tell us that tight control of hyperglycemia is not indicated in critically ill children following cardiac surgery. Although tight glycemic control lowered costs for other critically ill children, the long-term developmental effects of hypoglycemic episodes have to be determined before tight control becomes standard care ( http:// dx.doi.org /10.1056/nejme1313770 ). PREDICTING SUPPURATIVE COMPLICATIONS ASSOCIATEDWITH ACUTE SORE THROAT The suppurative complications that are associated with acute sore throat include quinsy (peritonsillar abscess), otitis media, and sinusitis. In a prospective cohort study on the website of the British Medical Journal ( http:// dx.doi.org /10.1136/bm j. f6867 ), researchers in the United Kingdom determined whether history and findings from physical examination predicted the suppurative complications that are associated with acute sore throat (with a duration of up to 2weeks) in nearly 15,000 adolescents and adults who were seen in primary care. About 1% of the patients developed suppurative complications, regardless of whether they got immediate antibiotics, no antibiotics, or delayed antibiotics. In a multivariate analysis, the independent predictors of suppurative complications were severe tonsillar inflammation and severe earache. But 70% of the suppurative complications happened when neither symptom was present. The results were similar when the analysis included only the patients who did not get antibiotics. This study of acute sore throat yielded several important findings. First, the suppurative complications that are associated with acute sore throat are not common. Second, history and physical examination findings cannot reliably predict which patients will develop suppurative complications. Third, although these findings were not correlated with culture data, getting antibiotics did not seem to alter the rate of suppurative complications. The researchers recommend that clinicians advise their patients with acute sore throats about the symptoms and signs of suppurative complications that should prompt reconsultation (like persistent fever and progressive difficulty with swallowing). DURATION OF ACUTE RESPIRATORY INFECTION SYMPTOMS IN OTHERWISE HEALTHY CHILDREN How long should clinicians expect symptoms to last in children who have acute respiratory tract infections? In a systematic review on the website of the British Medical Journal ( http:// dx.doi.org /10.1136/bm j. f7027 ), researchers evaluated nearly 50 trials and observational studies to determine the symptom durations of common acute respiratory tract infections in otherwise healthy children between birth and the age of 18. The eligible studies involved children who presented to primary care or emergency departments with acute earaches (acute otitis media), sore throats (pharyngitis or tonsillitis), coughs (bronchitis, bronchiolitis, or croup), common colds, or nonspecific upper respiratory infections, and provided data on the time to the resolution of these symptoms. Only data from placebo or no treatment groups were used. For 90% of the children, croup resolved in 2days, sore throats in 2days to 7days, earaches in 7days to 8days, common cold symptoms within 15days, symptoms of nonspecific upper respiratory infection within 16days, bronchiolitis within 21days, and acute cough within 25days. This systematic review provides evidence-based and practical data for advising and setting expectations for parents and others regarding symptom duration in children presenting with acute respiratory infections, which usually do not need treatment with antibiotics. We do not really know whether these findings apply to adults. Notably, the Centers for Disease Control and Prevention provide excellent information and advice for caregivers regarding these conditions, when to seek consultation, and when antibiotics might be indicated ( www. cdc .gov /GetSmart/antibiotic-use/URI/index.html ).

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Learning Format 6 Hours
Self-Study

Credit Type(s)
Internal Medicine Geriatrics Urology