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What's new in family medicine

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2014. | This topic last updated: Dec 12, 2014.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ADULT GENERAL INTERNAL MEDICINE

Combination of varenicline and nicotine patch improves smoking cessation rates (October 2014)

In a randomized trial, 435 smokers were assigned to treatment with varenicline combined with either a nicotine or a placebo patch [1]. Nicotine or placebo patches were started two weeks before the quit day and varenicline was started one week before the quit day. Both patches and varenicline were continued for 12 weeks. Treatment with varenicline and the nicotine patch resulted in a higher rate of continuous abstinence compared with varenicline and the placebo patch (49 versus 33 percent) at six months after the end of drug treatment. Prior studies have also shown higher rates of abstinence with the combination of nicotine replacement therapy (NRT) and bupropion, and with the combination of varenicline and bupropion. We continue to suggest initiating therapy with medication from a single class (eg, varenicline, bupropion, or NRT), given the increased cost and additional side effects with combining therapies, but combining medication classes is a reasonable option for patients who have failed initial therapy. (See "Pharmacotherapy for smoking cessation in adults", section on 'Patients who fail to quit'.)

Statin-associated adverse muscle events (October 2014)

Terminology around statin-associated adverse muscle events is variable and has changed over time. The 2014 National Lipid Association Statin Muscle Safety Task Force has proposed new definitions for these adverse events [2], which are reflected in our discussion of statin myopathy. Additionally, we no longer suggest a trial of Coenzyme Q10 (CoQ10) for patients experiencing such statin-associated adverse muscle events. (See "Statin myopathy", section on 'Coenzyme Q10' and "Statin myopathy", section on 'Definitions'.)

Acetaminophen in the treatment of acute low back pain (September 2014)

In a randomized trial of 1645 patients with acute low back pain (less than six weeks duration), there was no difference in recovery time or other measures of pain and function between patients treated with placebo, as-needed acetaminophen, and regular acetaminophen use [3]. Potential reasons for the apparent lack of effect include that some patients also used other treatments during the trial period and the actual amount of medicine (median dose of 2660 mg) taken may not have been sufficient. A treatment trial of acetaminophen for acute low back pain remains a reasonable treatment option. (See "Treatment of acute low back pain", section on 'Acetaminophen'.)

KEEPS hormone therapy trial in newly menopausal women (September 2014)

The Women's Health Initiative (WHI), a set of menopausal hormone therapy (MHT) trials in older postmenopausal women (average age 63 years) reported an excess risk of coronary heart disease (CHD) with MHT. Emerging data, including secondary analyses from the WHI, now suggest that use of MHT in the early menopausal years is not associated with excess CHD risk. The Kronos Early Estrogen Prevention Study (KEEPS) is the first randomized trial of MHT in younger menopausal women (727 women ages 45 to 54 years) [4]. When combined with cyclical monthly oral progesterone, low dose oral conjugated estrogen (0.45 mg daily) or transdermal estradiol (50 mcg daily) for four years relieved menopausal symptoms. While several markers of cardiovascular risk improved in the MHT group, there was no significant effect on surrogate markers of atherosclerosis progression (coronary artery calcium and carotid intima-medial thickness) when compared to placebo. This trial provides additional reassurance that early use of MHT is safe for the treatment of menopausal symptoms, though it does not support a role for MHT in prevention. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)

Epidural glucocorticoid injections not effective for lumbar spinal stenosis (August 2014)

The available evidence does not support the use of epidural injections of glucocorticoids in lumbar spinal stenosis (LSS). In a randomized trial of 400 patients with LSS, moderate to severe leg pain, and disability, those patients who received one or two epidural injections of glucocorticoids plus lidocaine had similar pain and disability outcomes at six weeks as those who received injections of lidocaine alone [5]. Adverse events (such as pain, headache, fever, and infection) were nonsignificantly higher in the glucocorticoid group (21.5 versus 15.5 percent). Since this study did not include a sham control group, it does not rule out a potential benefit from the injection of the local anesthetic. (See "Lumbar spinal stenosis: Treatment and prognosis", section on 'Epidural injections'.)

Oral emergency contraception in overweight women (August 2014)

In Europe, product labeling for levonorgestrel-based emergency contraception (NorLevo) was updated in February 2014 to indicate that it may be less effective in women ≥75 kg (165 pounds). In July 2014, the European Medicines Association concluded that the available data were not robust enough to be certain the contraceptive efficacy of levonorgestrel emergency contraception is reduced with increased bodyweight and that the benefits of taking the medication outweighed any risks [6]. We counsel overweight and obese women of potentially reduced efficacy of levonorgestrel emergency contraception as BMI increases above the normal range (25 kg/m2) or at weights ≥75 kg (165 pounds), and offer them a copper-releasing IUD as first-line therapy to prevent pregnancy. If the IUD is not an option, ulipristal is more likely to be effective than levonorgestrel. (See "Emergency contraception", section on 'Overweight and obese women'.)

Recurrence of Stevens-Johnson syndrome/toxic epidermal necrolysis (June 2014)

Although there are reports of recurrence of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), the overall risk of recurrence is unknown. In a 10-year population-based cohort of 708 patients hospitalized for a first episode of SJS or TEN, 7.2 percent of 581 survivors were hospitalized for a second episode and 1.4 percent had multiple recurrences; lack of direct access to medical records precluded information about medication exposures [7]. The median time to first recurrence was 315 days. The high risk of recurrence after a first episode of SJS/TEN may reflect a long-lasting vulnerability or a genetic predisposition to severe drug reactions. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Recurrence'.)

Oral contraceptives versus oral antibiotics for the treatment of acne vulgaris (June 2014)

Oral contraceptives and oral antibiotics are commonly used for the treatment of acne vulgaris in women, but studies directly comparing these treatments are lacking. The first meta-analysis to address this issue included randomized trials with at least one investigational arm that consisted of oral antibiotic or oral contraceptive treatment [8]. Efficacy data from individual trials were pooled. Compared with placebo, the two treatments yielded similar reductions in acne lesions after six months, but antibiotics had a faster onset of action. Given the heterogeneity in treatment protocols and patient populations, head-to-head trials are necessary to confirm these results. (See "Hormonal therapy for women with acne vulgaris", section on 'Comparison to oral antibiotic therapy'.)

GERIATRICS

Trimethoprim-sulfamethoxazole and sudden death (December 2014)

While trimethoprim-sulfamethoxazole (TMP-SMX) has generally been felt to be well tolerated, a case-control study found an association between sudden death, possibly due to hyperkalemia, and prescription of TMP-SMX among older patients who were also receiving an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) [9].Those who received TMP-SMX had an increased seven-day risk of sudden death compared with those who received amoxicillin (adjusted odds ratio 1.38, 95% CI 1.09-1.76). However, other factors that affected the choice of antibiotic may have confounded these results, and higher quality evidence is needed to determine whether this association is causal. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Life threatening effects'.)

CPAP therapy for older adults with obstructive sleep apnea (October 2014)

Continuous positive airway pressure (CPAP) is the mainstay of therapy for most adults with obstructive sleep apnea (OSA), but previous clinical trials have enrolled primarily younger adults. In a multicenter trial that included 278 adults ≥65 years of age with newly diagnosed OSA, patients randomized to receive CPAP therapy plus best supportive care had improvement in daytime sleepiness compared with those assigned to best supportive care alone [10]. The benefits of CPAP were present at both three- and 12-month time points and were greater in those with higher CPAP usage and higher baseline sleepiness scores. Secondary endpoints, including quality of life, mobility, cognitive function, and cardiovascular events, were similar between groups. A major limitation of the trial was the lack of a sham CPAP control arm. (See "Sleep apnea and other causes of impaired sleep in older adults", section on 'Treatment'.)

PREVENTION

Pneumococcal conjugate vaccine in adults ≥65 years of age (September 2014)

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults ≥65 years of age. In September 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending the pneumococcal conjugate vaccine (PCV13) for all adults ≥65 years of age [11]. Current recommendations for individuals ≥65 years of age who have not previously received either PCV13 or PPSV23 are to administer PCV13 followed 6 to 12 months later by PPSV23 (algorithm 1). In patients who have already received PPSV23, at least one year should elapse before they are given PCV13.

The ACIP revision was prompted by results from the CAPiTA trial. This randomized placebo-controlled trial, including approximately 85,000 adults ≥65 years of age in the Netherlands, demonstrated the efficacy of PCV13 against vaccine-type pneumococcal pneumonia, vaccine-type nonbacteremic pneumococcal pneumonia, and vaccine-type invasive pneumococcal disease [12]. However, some concern has been raised that since this trial began before PCV13 was used routinely in infants in the Netherlands, it might not answer the question of whether its use in adults is efficacious in countries that routinely vaccinate infants. (See "Pneumococcal vaccination in adults", section on 'Indications'.)

Niacin in combination with statins (July 2014)

The HPS2-THRIVE trial examined extended-release niacin plus laropiprant (a selective prostaglandin D2 receptor antagonist, given to reduce flushing from niacin) compared with placebo in patients with known cardiovascular disease who were being treated with simvastatin; some patients also received ezetimibe [13]. After a median follow-up of 3.9 years, there was no reduction with niacin/laropiprant in the primary endpoint of first major vascular event, but there was a statistically nonsignificant increase in mortality (6.2 versus 5.7 percent). Additionally, and despite a run-in period, there was an increase in serious adverse events that included myopathy, with a much greater increased risk in patients from study centers in China than in Europe, and worsened glucose control with both an increase in new cases of diabetes and serious disturbance in diabetes control that typically led to hospitalization. Additionally, there were increases in serious infections (8.0 versus 6.6 percent) and bleeding (2.5 versus 1.9 percent).

It is not possible to determine which effects were due to laropiprant, niacin, or the combination of the two drugs. Given these results, infection and bleeding were subsequently examined in the earlier AIM-HIGH trial, which studied niacin without laropiprant [14]. Infections were increased with niacin (8.1 versus 5.8 percent), and there were only small numbers to assess rates of bleeding (3.4 versus 2.9 percent; p = 0.36). The most likely interpretation of these results is that the observed adverse effects were primarily due to niacin. Given these results, we would not administer niacin to most patients receiving statin therapy. The balance of safety and efficacy of niacin monotherapy is also unclear. (See "Lipid lowering with drugs other than statins and fibrates", section on 'Nicotinic acid (Niacin)'.)

SCREENING

Flexible sigmoidoscopy for colorectal cancer screening (August 2014)

The Norwegian Colorectal Cancer Prevention (NORCCAP) trial randomly assigned individuals aged 50 to 64 years to one time flexible sigmoidoscopy screening (n = 20,572) or no screening (n = 78,220) [15]. One-half of those assigned to sigmoidoscopy screening were also assigned to an immunochemical fecal occult blood test (iFOBT). Screening adherence was 63 percent. After a median follow-up of 10.9 years, there was a decrease in deaths from colorectal cancer in the flexible sigmoidoscopy screening group compared to the control group (31.4 versus 43.1 deaths per 100,000 person years). There was no difference between those who did or did not have additional iFOBT testing. A difference in mortality outcomes was not demonstrable until the ninth year of follow-up. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Evidence of effectiveness'.)

Thirteen-year follow-up data on prostate cancer screening (August 2014)

Thirteen-year follow-up data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) provides additional insights on the long-term implications of screening men aged 50 to 74 years for prostate cancer [16]. Given the indolent course of prostate cancer, shorter-term follow-up from the trial may have been insufficient to accurately estimate the survival benefit. However, the absolute rate reduction in prostate cancer deaths for patients randomized to screening has changed only minimally, comparing rates after 9 and 13 years of follow-up (0.06 fewer deaths versus 0.11 fewer deaths per 1000 person years, respectively). This is equivalent to needing to invite 781 men for screening to prevent one prostate cancer death after 13 years. Furthermore, while the prostate cancer survival benefit from screening was not initially realized until nine years of follow up [17], the burdens of screening and treatment, including harms from overdiagnosis and overtreatment, occur immediately and potentially have lifelong consequences. (See "Screening for prostate cancer", section on 'Evidence from randomized trials'.)

Colorectal cancer screening in older adults who have never been screened (July 2014)

For most older adults, it is reasonable to stop screening for colorectal cancer (CRC) at age 75 years, or 85 years at the latest. However, for older adults who have never been screened for CRC (23 percent of US elderly individuals), one-time screening appears to be cost-effective up to age 86 years, based on results of a modeling study [18]. In this simulation study, assuming a willingness to pay $100,000 per quality-adjusted life-year gained, colonoscopy was cost-effective to age 83 years, sigmoidoscopy to 84 years, and fecal immunochemistry testing to 86 years for patients without comorbidity and at average risk for CRC. Colonoscopy was the most effective, and most expensive, strategy for one-time screening. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'Older adults with no prior screening'.)

Breast cancer screening with tomosynthesis and mammography (July 2014)

A retrospective study in women from diverse populations in the United States, in both community and academic settings, compared digital mammography alone (n = 280,000) with digital mammography plus tomosynthesis (n = 174,000) [19]. Examinations were performed in two different time periods, and women were not randomly assigned to one or another group. Tomosynthesis plus digital mammography was associated with fewer recalls for suspicious findings, a slightly higher detection rate of invasive cancer, and a higher positive predictive value for recall and for biopsy. However, tomosynthesis increases radiation exposure and there are no prospective large studies with patient outcomes to justify its routine use at the present time. (See "Breast imaging for cancer screening: Mammography and ultrasonography", section on 'Tomosynthesis' and "Screening for breast cancer: Evidence for effectiveness and harms", section on 'Tomosynthesis'.)

Screening for Hepatitis B virus infection in the United States (June 2014)

Infection with Hepatitis B virus (HBV) can lead to chronic liver disease and is preventable with vaccination. The US Preventive Services Task Force (USPSTF) has updated its statement on screening for HBV infection in nonpregnant adolescents and adults to recommend that individuals at high-risk for HBV infection be screened if they have not been vaccinated or if they were vaccinated without prior screening [20]. High-risk populations include persons born in regions with a prevalence of HBV ≥2 percent, US–born persons whose parents were born in regions with a prevalence ≥8 percent, injection drug users, men who have sex with men, household contacts of persons with HBV infection, and individuals with HIV infection. Existing guidelines from the Centers for Disease Control and Prevention and the American Association for the Study of Liver Disease also support screening of high-risk individuals in the US. (See "Diagnosis of hepatitis B virus infection", section on 'Who should be tested or screened'.)

Anxiety related to false-positive screening mammograms (June 2014)

Concern has been raised about the psychological consequences of false-positive screening mammograms. In a study that compared anxiety scores, assessed by telephone survey shortly after mammography and one year subsequently, for women with and without false-positive mammograms, anxiety was higher for women with false-positive mammography at the initial survey, but there was no significant difference between groups at one year [21]. Women who had a false-positive mammogram, compared with women without false-positive results, reported a greater likelihood of future screening. Women who participated in this study were volunteer participants in a randomized trial comparing types of mammogram screening and may have been more committed to screening than the general population. (See "Screening for breast cancer: Evidence for effectiveness and harms", section on 'Anxiety related to false-positive findings'.)

ADULT CARDIOVASCULAR MEDICINE

Optimal duration of dual antiplatelet therapy after coronary stenting (December 2014)

All patients who undergo percutaneous coronary intervention with stenting receive dual antiplatelet therapy (DAPT), which is the combination of aspirin and a P2Y12 receptor blocker. However, the optimal duration of DAPT is not known; 12 months has been the commonly recommended duration. The DAPT trial randomly assigned 9961 such patients, who had been successfully treated with 12 months of aspirin and a P2Y12 receptor blocker (either clopidogrel or prasugrel), to continue receiving the P2Y12 receptor blocker or placebo for another 18 months; all patients continued aspirin [22]. The rates for each of the co-primary end points of stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death from any cause, MI, or stroke) were lower with continued P2Y12 therapy (0.4 versus 1.4 percent and 4.3 versus 5.9 percent). However, the rate of moderate or severe bleeding was increased (2.5 versus 1.6 percent). Based on available evidence, including the DAPT trial, we recommend DAPT for 12 months in patients not at high risk of bleeding, which is the major complication of this therapy. After 12 months of uncomplicated DAPT therapy, we suggest an additional 18 months of treatment. (See "Antiplatelet therapy after coronary artery stenting", section on 'Drug-eluting stents'.)

Genetic predisposition to hyperlipidemia associated with aortic valve disease (December 2014)

Plasma low-density lipoprotein cholesterol (LDL-C) is associated with risk of calcific aortic valve disease but the genetic contribution to this risk is uncertain. A Mendelian randomization study found an association between the weighted genetic risk score (GRS, a measure of the genetic predisposition to elevation in plasma lipids) for low-density lipoprotein cholesterol (LDL-C) and aortic valve calcium in 6942 participants in community-based studies [23]. The LDL-C GRS was also associated with incident aortic stenosis in a separate community-based population. Trials of lipid lowering therapies in patients with aortic stenosis have not shown convincing benefit but the potential effect of lipid lowering therapy initiated earlier is uncertain. (See "Aortic valve sclerosis and pathogenesis of calcific aortic stenosis", section on 'Genetic factors'.)

Risk of myocardial infarction and nonobstructive coronary heart disease (November 2014)

Given the slow progression of atherosclerosis, patients with coronary heart disease (CHD) may be asymptomatic for years, and the prognosis related to nonobstructive coronary lesions is uncertain. Nonobstructive CHD refers to stenosis ≥20 percent but <70 percent, while obstructive CHD is identified when at least one stenosis is ≥70 percent. In a retrospective cohort study of over 37,000 patients (96 percent male) without prior CHD events who underwent elective coronary angiography and were followed for one year, the risk of myocardial infarction (MI) increased with the extent of both nonobstructive and obstructive lesions [24]. Compared to patients without CHD, the risk of MI trended higher for patients with one vessel nonobstructive CHD and was significantly greater for two and three vessel nonobstructive CHD. Patients found to have nonobstructive CHD should be treated with usual secondary prevention measures. (See "Epidemiology of coronary heart disease", section on 'Non-obstructive CHD'.)

Lower risk of fatal bleeding with target specific oral anticoagulants versus warfarin (November 2014)

All anticoagulants carry a risk of bleeding, and the lack of an antidote for direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and the direct thrombin inhibitor dabigatran increases concerns about this risk. Reassuringly, a meta-analysis of 12 randomized trials in patients with atrial fibrillation or venous thromboembolism that compared bleeding risk with these agents versus vitamin K antagonists found lower rates of fatal bleeding, major bleeding, and intracranial bleeding with the direct factor Xa and direct thrombin inhibitors [25]. Individual patient factors continue to play a role in anticoagulant choice and the development of reversal agents for the factor Xa and thrombin inhibitors is underway. (See "Management of bleeding in patients receiving target-specific oral anticoagulants", section on 'Risk of bleeding'.)

The role of digoxin in rate control for patients with AF (August 2014)

The role of digoxin in ventricular rate control in patients with atrial fibrillation (AF) has been limited due to relative poor efficacy and the possibility of an increase in mortality in patients without heart failure. The observational TREAT-AF study evaluated mortality in over 120,000 patients with a recent diagnosis of nonvalvular atrial fibrillation [26]. In this new study, digoxin use was associated with a nearly 25 percent increase in all-cause mortality across all subgroups, including those with and without heart failure. Important limitations of this study include its retrospective design and the absence of a detailed evaluation of the potential impact of digoxin levels. We limit the use of digoxin in AF patients without heart failure to those in whom beta blockers and calcium channel blockers have not achieved adequate rate control and who are not considered candidates for non-pharmacologic therapy to control rate. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy", section on 'Digoxin'.)

Beta blockers in stable coronary heart disease (August 2014)

Although beta blocker therapy improves survival in patients who have sustained an acute myocardial infarction (MI), there is no convincing evidence for this benefit in patients with stable disease. In an observational study of over 26,000 patients discharged after a first coronary heart disease event (an acute coronary syndrome or coronary artery revascularization) and followed for nearly four years, there was no difference in the risk of death in the subgroup without recent MI between those who did or did not receive beta blocker [27]. In patients with stable coronary heart disease who have not had a recent acute MI, beta blockers are indicated to treat angina but not to improve survival. (See "Secondary prevention of cardiovascular disease", section on 'Beta blockers'.)

Running and cardiovascular risk (August 2014)

Several professional society guidelines recommend at least 30 minutes of moderate-intensity exercise five to seven days per week, but this is not achievable for all patients. In a prospective cohort study with a mean follow-up of over 15 years, over 55,000 adults (mean age 44 years) reported duration, distance, frequency, and speed of any running or jogging [28]. Runners had significantly lower risks of all-cause and cardiovascular mortality compared to non-runners. Additionally, the derived mortality benefit was similar for all runners regardless of the total running time, including for those who ran less than 51 minutes per week. These findings from a non-randomized study may represent unidentified confounding factors, and do not prove causation. However, these data support the concept that even small amounts of exercise are better than no exercise while at least 30 minutes of moderate-intensity exercise five to seven days per week remains a reasonable goal for most patients. (See "Exercise and fitness in the prevention of cardiovascular disease", section on 'Type, intensity, and duration of exercise'.)

Prophylactic ICD implantation for patients with LVEF 30 to 35 percent (July 2014)

Although most studies of prophylactic implantable cardioverter-defibrillator (ICD) implantation have included patients with a left ventricular ejection fraction (LVEF) ≤35 percent, most study patients had LVEF <30 percent, resulting in uncertainty regarding benefit in patients with LVEF between 30 and 35 percent. In a retrospective cohort study using data from two large registries of patients with and without ischemic disease (National Cardiovascular Data Registry of patients who underwent ICD implantation and Get With The Guidelines-Heart Failure patients without an ICD) in which the benefits of ICD implantation were separately evaluated for patients with LVEF <30 percent and those with LVEF 30-35 percent, all-cause mortality was significantly lower in patients with an ICD and any level of LVEF, compared with those without an ICD [29]. These data, although not from a randomized trial, support our recommendation to implant an ICD in patients with heart failure and an LVEF of 35 percent or lower. (See "Primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'LVEF and risk'.)

Bleeding risk with heparin or rivaroxaban increased by concomitant NSAID use (June 2014)

The bleeding risk of adding antiplatelet agents to anticoagulants has not been well quantified. A prospective analysis of over 8000 patients treated for venous thromboembolism with low molecular weight heparin or rivaroxaban (an oral direct factor Xa inhibitor) found a higher rate of major bleeding in patients also receiving an NSAID or aspirin compared with an anticoagulant alone (6.5 versus 2.0 bleeds per 100 patient-years) [30]. Gastrointestinal bleeds accounted for only 14 percent of clinically relevant bleeds. (See "Therapeutic use of heparin and low molecular weight heparin", section on 'Bleeding and protamine reversal'.)

ADULT ENDOCRINOLOGY AND DIABETES

Long-term effect of intensive glycemic control on macrovascular outcomes in type 2 diabetes (October 2014)

The ADVANCE trial randomly assigned 11,140 patients with long-standing type 2 diabetes to either standard therapy or modified release gliclazide plus other drugs as required to achieve an A1C of <6.5 percent, and found no benefit of intensive therapy on the primary composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke after a median of five years. Of the 10,082 surviving trial participants, 8494 enrolled in a post-trial monitoring study [31]. A 2000-patient random subset of the surviving cohort that agreed to participate in the post-trial monitoring study had periodic laboratory testing for A1C, fasting blood glucose, serum creatinine, blood pressure, and weight. Mean A1C, which had been significantly different during the trial, became similar by the first post-trial visit and remained similar throughout the monitoring period (7.2 and 7.4 percent in the original intensive and standard groups, respectively). After a median total follow-up of 9.9 years, similar to the findings in the randomized trial, there was no benefit of intensive therapy on macrovascular outcomes. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'ADVANCE'.)

Combination bupropion-naltrexone for the treatment of obesity (October 2014)

In September 2014, the combination of bupropion-naltrexone was approved in the United States by the Food and Drug Administration (FDA) as an adjunct to diet and exercise in patients with BMI ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least one weight-related comorbidity [32]. Because bupropion-naltrexone can raise blood pressure and heart rate, the FDA is requiring post-marketing studies to evaluate cardiovascular outcomes and the effect of the combination on cardiac conduction. Pending these further studies, we prefer to use orlistat or lorcaserin when medical treatment of obesity is indicated, rather than bupropion-naltrexone. (See "Obesity in adults: Drug therapy", section on 'Bupropion-naltrexone'.)

Long-term effect of antihypertensive therapy in diabetic patients (October 2014)

The ADVANCE trial randomly assigned 11,000 diabetic patients to a fixed combination of perindopril-indapamide or placebo for approximately four years. The trial included both patients with and without hypertension, and concomitant therapy with other blood pressure medication during the trial was at the discretion of the patient's physician. Patients in the perindopril-indapamide group had lower rates of cardiovascular mortality (3.8 versus 4.6 percent) and all-cause mortality (7.3 versus 8.5 percent). A post-trial, open-label cohort (8500 patients) were followed for an additional six years [31]. Blood pressures between the treatment and placebo groups, which were different during the trial (135/74 versus 140/76 mmHg), became similar within six months after completion of the trial and remained similar throughout the cohort phase. Compared with those originally assigned placebo, those who had received perindopril-indapamide had a lower death rate during the cohort phase (15.3 versus 16.7 percent), as well as a lower incidence of major cardiovascular events (13.3 versus 14.2 percent). Combining both the trial and cohort phases together (approximately 10 years of follow-up), all-cause mortality was significantly lower among those in the treatment group (hazard ratio 0.91, 95% CI 0.84-0.99). Thus, blood pressure lowering is associated with long-term benefits on mortality and cardiovascular disease in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'ADVANCE trial'.)

Weight loss diets (September 2014)

If adhered to, any diet that reduces caloric intake below expenditure will result in weight loss that is related to the energy deficit. This was illustrated by the findings of a meta-analysis of 48 randomized trials (7286 individuals) comparing different dietary programs (predominantly low carbohydrate, moderate macronutrient, or low fat) with a comparator (no diet or competing dietary program) [33]. Compared with no diet, all diet programs resulted in significant weight loss (approximately 6 to 8 kg at six months). At 12-month follow-up, the average weight losses of all diet programs were 1 to 2 kg less than at six-month follow-up. Weight loss differences between individual diets were minimal. (See "Obesity in adults: Dietary therapy", section on 'Weight loss diets'.)

GLP-1 receptor agonists for the treatment of type 2 diabetes (July 2014)

Albiglutide and dulaglutide are new long-acting (administered by subcutaneous injection once weekly) glucagon-like peptide-1 (GLP-1) receptor agonists available for use in the United States and Europe as monotherapy (in addition to diet and exercise) or in combination with metformin, glimepiride, or pioglitazone in adults with type 2 diabetes [34-37]. The side effect profiles are similar (nausea, vomiting, and diarrhea). We do not consider GLP-1 receptor agonists to be first-line therapy, but they can be prescribed in combination with metformin (and/or another oral agent) for patients who fail initial therapy with one or two oral agents, particularly when weight loss or avoidance of hypoglycemia is a primary consideration, the A1C level is close to target, and cost is not a major barrier. Among the long-acting GLP-1 agonists, patient preference and payer coverage are important considerations in choosing an agent. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Albiglutide'.)

Inhaled insulin (July 2014)

In June of 2014, the US Food and Drug Administration (FDA) approved a formulation of inhaled insulin (Afrezza) to improve glycemic control in adults with diabetes mellitus [38]. The approval includes a Risk Evaluation and Mitigation Strategy, which consists of informing healthcare professionals about the serious risk of acute bronchospasm associated with use in patients with asthma or other chronic lung diseases. Because of this risk, Afrezza is contraindicated in patients with chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD). Afrezza, which is administered at the beginning of a meal, is expected to become available for clinical use in early 2015. Until more published data about safety and efficacy are available, the role of this insulin preparation is uncertain. (See "Inhaled insulin therapy in diabetes mellitus", section on 'Dose and administration'.)

Automated closed-loop insulin pump (July 2014)

Small studies have compared overnight glycemic control using a fully automated closed-loop system of insulin delivery (eg, patients do not adjust dosing) with conventional insulin pump therapy. In two crossover trials in adults and adolescents, an automated bihormonal (insulin and glucagon) closed-loop system was compared with conventional insulin pump therapy over a five-day period [39]. The delivery of insulin and glucagon during the closed-loop arm was determined automatically by an algorithm that adjusted doses based on continuous glucose monitoring. On days 2 through 5 of the closed-loop system, as compared with the control period, the mean glucose level was lower in both adults and adolescents. There were no severe hypoglycemic events during the closed-loop period. Although these preliminary results are promising, additional trials are needed. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Automated closed-loop insulin pump'.)

Testosterone products: Revised labeling for venous thromboembolism risk (July 2014)

While previous labeling of testosterone products in the United States has included information about the risk of venous thromboembolism (VTE) as a consequence of erythrocytosis, a recent study found that venous thromboses and pulmonary emboli may occur unrelated to polycythemia in patients taking testosterone [40]. In this study, among 40 men who had thrombotic events at a median of five months after starting testosterone therapy, 39 were found to have previously undiagnosed thrombophilia-hypofibrinolysis, highlighting the importance of a careful personal and family VTE history prior to initiating treatment. Routine screening for thrombophilias in men considering testosterone therapy is not currently suggested. The US Food and Drug Administration (FDA) will now require a more general warning about the risk of thrombosis in the labeling of all approved testosterone products [41]. (See "Testosterone treatment of male hypogonadism", section on 'Erythrocytosis' and "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism'.)

Nasal testosterone gel for male hypogonadism (June 2014)

The first nasal testosterone gel (Natesto) has been approved in the United States for the treatment of male hypogonadism [42]. The gel is administered into the nostrils via a metered-dose pump applicator. One advantage over other formulations is the minimal risk of gel transfer to a partner or child. On the other hand, some men may find the three times daily regimen inconvenient, and those with allergies or underlying nasal or sinus pathology may have trouble tolerating the formulation as rhinorrhea, nasopharyngitis, and sinusitis are among the most common side effects. Until further published data are available, we suggest using other available testosterone gels, patches, or injectable esters over this new formulation. (See "Testosterone treatment of male hypogonadism", section on 'Other'.)

ADULT GASTROENTEROLOGY

Intermittent dosing of proton pump inhibitors for peptic ulcer bleeding (October 2014)

Treatment with proton pump inhibitors (PPIs) leads to elevation of gastric pH levels, which stabilizes blood clots and improves clinical outcomes. As a result, PPIs are recommended for all patients with peptic ulcer bleeding. High-dose continuous infusions of intravenous (IV) PPIs have traditionally been recommended for patients presenting with upper gastrointestinal bleeding. However, several meta-analyses of randomized trials have failed to show superior outcomes with high-dose continuous IV proton pump administration compared with intermittent dosing (eg, 40 mg IV twice daily). In addition, intermittent dosing could lead to decreased resource utilization and cost. In the most recent meta-analysis, intermittent dosing was not inferior to high-dose continuous infusions with regard to rebleeding, mortality, need for surgery or repeat intervention, or the need for urgent intervention in patients with peptic ulcers with high-risk stigmata (active bleeding, adherent clot, or a visible vessel) [43]. There was also a trend toward a decreased risk of rebleeding with intermittent dosing. Based on this cumulative evidence, for patients presenting with upper gastrointestinal bleeding, we now recommend treatment with IV pantoprazole, esomeprazol, or omeprazole (where available) at a dose of 40 mg twice daily rather than a high-dose continuous infusion. (See "Overview of the treatment of bleeding peptic ulcers", section on 'Summary and recommendations' and "Overview of the treatment of bleeding peptic ulcers", section on 'Continuous versus intermittent dosing'.)

Ledipasvir-sofosbuvir for genotype 1 chronic hepatitis C infection (December 2013, MODIFIED October 2014)

Interferon-free options for chronic genotype 1 hepatitis C virus (HCV) infection are increasing. A once-daily combination pill of two direct-acting antiviral agents, ledipasvir and sofosbuvir, is becoming available in the United States and elsewhere. In several large open-label trials, ledipasvir-sofosbuvir achieved sustained virologic response (SVR) rates exceeding 90 percent in genotype 1 infected patients regardless of treatment history or presence of cirrhosis [44-46]. For all patients with chronic genotype 1 HCV infection, we favor the regimen of ledipasvir-sofosbuvir because of its efficacy, its favorable adverse effect profile, its ease of administration, and extensive data to support its use. For treatment-naïve patients, treatment duration is eight weeks for those without cirrhosis and a viral level <6 million international units/mL, and 12 weeks for those with cirrhosis or a higher viral level. For treatment-experienced patients, treatment duration is 12 weeks for those without cirrhosis and 24 weeks for those with cirrhosis. (See "Treatment regimens for chronic hepatitis C virus genotype 1", section on 'Selection of treatment regimens'.)

ADULT HEMATOLOGY AND ONCOLOGY

Chemohormonal therapy for metastatic prostate cancer (June 2014)

Historically, androgen deprivation therapy (ADT) has been the initial therapy for men with metastatic prostate cancer, and docetaxel chemotherapy has been reserved for patients with castration-resistant disease. In the CHAARTED trial, men with no prior hormonal therapy for metastatic prostate cancer (castration-sensitive disease) were randomly assigned to ADT plus docetaxel or to ADT alone [47]. Initial chemohormonal therapy with the combination produced a statistically significant and clinically meaningful improvement in overall survival compared with ADT alone. Based on these results, we recommend chemohormonal therapy for men with castration-sensitive, high-volume metastatic prostate cancer. (See "Initial therapy for castration sensitive metastatic prostate cancer", section on 'Chemohormonal therapy'.)

ADULT INFECTIOUS DISEASE

Circulating influenza A H3N2 viruses in the United States (December 2014)

In December 2014, the CDC released a health advisory stating that more than half of influenza A H3N2 viruses collected and analyzed in the United States in October and November 2014 were antigenically different (drifted) from the H3N2 antigen included in this season's influenza vaccines [48]. Although influenza has been relatively infrequent up to this point in the season, it appears to be increasing, and most isolated influenza viruses have been H3N2 strains. During previous seasons in which influenza A H3N2 viruses have predominated, higher hospitalization and mortality rates have been reported among older people, very young children, and individuals with certain medical conditions. Influenza vaccination is still strongly recommended because it usually provides some cross-protection against drifted viruses and because influenza vaccines protect against other strains. The CDC health advisory was issued to reemphasize the importance of the use of neuraminidase inhibitors (eg, oseltamivir, zanamivir) when indicated for the treatment and prevention of influenza infection as an adjunct to vaccination. (See "Seasonal influenza vaccination in adults", section on 'Drifted H3N2 viruses during the 2014 to 2015 influenza season'.)

ACIP recommendations for the 2014-2015 influenza season (August 2014)

In August 2014 the United States Advisory Committee on Immunization Practices (ACIP) released updated recommendations for the prevention of seasonal influenza with vaccines [49]. Important changes from previous recommendations include:

A preferential recommendation for the nasal spray vaccine (live attenuated influenza vaccine, LAIV) over the intramuscular injection (inactivated influenza vaccine, IIV) for children two through eight years of age who do not have specific contraindications to the nasal vaccine (eg, asthma, egg allergy, diabetes, immunosuppression). UpToDate agrees with this recommendation, but also prefers LAIV for children older than eight years. If LAIV is not immediately available, IIV should be administered to avoid missing an opportunity for influenza immunization. (See "Seasonal influenza in children: Prevention with vaccines", section on 'LAIV compared with IIV'.)

Changes to the dosing schedule for children six months through eight years of age (algorithm 2). (See "Seasonal influenza in children: Prevention with vaccines", section on 'Schedule'.)

Recommendations for adults are largely unchanged. (See "Seasonal influenza vaccination in adults", section on 'Overview'.)

Efficacy of high-dose influenza vaccine in elderly adults (August 2014)

Due to concern that standard-dose influenza vaccines may be less effective in elderly adults than in younger adults, a high-dose influenza vaccine, Fluzone high-dose, has been developed. In a trial that included more than 30,000 adults ≥65 years of age, Fluzone high-dose was modestly more effective than standard-dose Fluzone [50]. Among individuals in the high-dose group, 1.4 percent had laboratory-confirmed influenza associated with an influenza-like illness compared with 1.9 percent in the standard-dose group (relative efficacy 24.2 percent). The rates of serious adverse events were similar with the high-dose and standard-dose vaccines. For individuals ≥65 years of age, we prefer Fluzone high-dose when available rather than a standard-dose inactivated vaccine. However, the United States Advisory Committee on Immunization Practices has not stated a preference for Fluzone high-dose over the standard-dose inactivated influenza vaccine in older adults [49,51]. (See "Seasonal influenza vaccination in adults", section on 'High-dose vaccine' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation'.)

Testing algorithms to diagnose HIV infection (July 2014)

We agree with new recommendations from the United States Centers for Disease Control and Prevention (CDC) to use a combination assay that detects HIV antigen and antibodies as the initial test for laboratory-based HIV screening and diagnosis for patients two years and older (algorithm 3) [52]. If the initial test is reactive, an HIV-1/HIV-2 differentiation assay should be performed as a confirmatory test. Testing with an antibody-only assay followed by a confirmatory Western blot is no longer recommended. In comparison, the new algorithm is better able to diagnose acute infection when antibody may not yet be detectable (eg, "window period of acute HIV infection") and can provide information as to whether the patient is infected with HIV-1, HIV-2, or both. Reactive rapid antibody tests performed in community-based settings should be confirmed using this new algorithm as well. (See "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)

Next-generation DNA sequencing for pathogen identification (June 2014)

Next-generation sequencing (NGS) is a method for determining DNA sequence by analyzing multiple DNA fragments in parallel; it allows sequencing of an exponentially greater number of genes than conventional DNA sequencing. Although NGS has been applied to the diagnosis of complex genetic disorders, a new report suggests it may also be helpful in identifying an infectious pathogen when microbial or serologic testing is unrevealing [53]. NGS was performed on the cerebrospinal fluid of a 14-year-old boy with unexplained fever and progressive neurologic deterioration in whom an extensive infectious disease evaluation had been negative. A species of Leptospira was identified, and antibiotic therapy was initiated with rapid clinical improvement. Subsequent testing confirmed the diagnosis. (See "Principles and clinical applications of next-generation DNA sequencing", section on 'Indications for next-generation sequencing'.)

Cardiovascular outcomes and azithromycin use for pneumonia (June 2014)

Large observational studies have shown conflicting results with regards to a possible increase in cardiovascular mortality associated with azithromycin use. A more recent large cohort study evaluated the association between azithromycin use and all-cause mortality and cardiovascular events in more than 60,000 United States veterans ≥65 years of age who were hospitalized with pneumonia [54]. Ninety-day mortality was significantly lower in those who were treated with an azithromycin-containing regimen versus those who received other guideline-concordant antibiotics. Compared with patients who did not receive azithromycin, those who received azithromycin were slightly more likely to have a myocardial infarction, but not arrhythmias, heart failure, or any cardiac event. An analysis of these data suggested that seven deaths were averted for each non-fatal myocardial infarction associated with azithromycin use, reflecting a net benefit of azithromycin for patients ≥65 years of age with pneumonia. (See "Azithromycin, clarithromycin, and telithromycin", section on 'QT interval prolongation and cardiovascular events'.)

Guidelines on pre-exposure prophylaxis for HIV prevention (June 2014)

Pre-exposure prophylaxis (PrEP) with daily use of tenofovir-emtricitabine, a combination antiretroviral agent, can reduce the risk of HIV acquisition in uninfected individuals who are at high risk of infection. In 2014, the US Public Health Service formally released clinical practice guidelines to help providers decide which patients may benefit from PrEP [55]. The guidelines also advise on the evaluation and monitoring of patients who decide to initiate PrEP. To optimize the efficacy of PrEP, they stress the importance of a comprehensive approach to care that includes HIV testing prior to and during treatment, as well as adherence and risk reduction counseling. UpToDate recommendations are largely consistent with these guidelines. (See "Pre-exposure prophylaxis against HIV infection", section on 'Approach to pre-exposure prophylaxis against HIV'.)

New antibiotics with activity against MRSA for skin and skin structure infections (June 2014, MODIFIED June 2014)

Antibiotic options for the treatment of skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are growing. Dalbavancin and oritavancin have a similar mechanism of action and spectrum of activity to vancomycin, but can be administered as once-weekly intravenous doses because of long half-lives. Tedizolid is from the same antibiotic class as linezolid and can be administered intravenously or orally once daily. In several large randomized trials of adults with acute cellulitis, wound infections, and abscesses, including infections caused by MRSA, these new agents had efficacy and safety profiles similar to vancomycin and/or linezolid with more convenient dosing [56-58]. Dalbavancin, tedizolid, and oritavancin have been approved for skin and skin structure infections by the U.S. Food and Drug Administration in 2014. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on 'Dalbavancin' and "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on 'Oritavancin'.)

ADULT NEPHROLOGY AND HYPERTENSION

Risk of gestational hypertension or preeclampsia in kidney donors (November 2014)

The assessment of risk conferred by living kidney donation is critically important in determining the suitability of individual donor candidates. A retrospective cohort study demonstrated an increased risk of gestational hypertension or preeclampsia compared with well-matched nondonors [59]. Women of childbearing age who wish to donate a kidney should be advised of this increased risk. (See "Evaluation of the living kidney donor and risk of donor nephrectomy", section on 'Maternal and fetal outcomes'.)

Initial imaging in patients with suspected nephrolithiasis (September 2014)

Computerized tomography (CT) and ultrasonography as initial imaging strategies were compared in a large multicenter randomized trial [60]. Patients presenting to an emergency department (ED) with suspected nephrolithiasis (but without signs of another serious diagnosis) were assigned to initial imaging with a non-contrast helical CT scan, ultrasonography performed by a radiologist, or ultrasonography performed at the bedside by an ED physician. Subsequent evaluation and care was at the discretion of the treating clinicians. The sensitivity for stone detection was lower for ultrasonography than CT scan (54 percent if performed by an ED physician or 57 percent performed by a radiologist compared with 88 percent for CT). A CT scan was performed in 41 percent of patients who initially underwent ultrasonography while 5 percent of patients who initially had a CT subsequently had ultrasonography. Despite the lower sensitivity of ultrasonography, the rates of important missed diagnoses that resulted in complications, such as pyelonephritis with sepsis or diverticular abscess, were similar (0.5 percent with ultrasonography versus 0.3 percent with CT). Serious adverse events and return visits to the ED after discharge were also similar. Patients assigned to receive an initial CT were exposed to more than twice as much radiation during the initial ED visit than those assigned ultrasonography although, because many patients assigned ultrasonography ultimately underwent CT, the differences in cumulative radiation exposure at six months were less dramatic. While we previously suggested a non-contrast helical CT scan as the test of choice for most patients with suspected nephrolithiasis, we now consider that both CT and ultrasonography are acceptable initial imaging modalities in patients with suspected nephrolithiasis who have a low clinical suspicion for an alternative serious diagnosis. In such patients, ultrasonography leads to less radiation exposure than CT and equivalent overall outcomes. (See "Diagnosis and acute management of suspected nephrolithiasis in adults", section on 'Tests of choice: Non-contrast CT scan or ultrasonography'.)

ADULT NEUROLOGY AND PSYCHIATRY

Rising number of opioid overdoses in US (November 2014)

Rising rates of opioid use and addiction in recent years have had significant clinical consequences. A study of nationally representative data on US emergency department (ED) visits has found that approximately 731,000 ED visits for opioid overdose occurred from 1993 to 2010; the population-based rate of ED visits for opioid overdose nearly quadrupled over this time period [61]. Increases in overdose rates were seen with both pharmaceutical and non-pharmaceutical opioids. These findings suggest that programs implemented to combat opioid abuse and misuse in the US have been insufficient. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Overdose'.)

Risk of elective noncardiac surgery after acute stroke (September 2014)

Elective surgery should be deferred when possible in the setting of an acute stroke, as adverse outcomes are likely to be increased in this setting. In a Danish nationwide cohort study, the risk of major adverse cardiovascular events (ischemic stroke, acute myocardial infarction, and cardiovascular mortality) and 30-day all-cause mortality was significantly higher in patients with a history of recent stroke [62]. Compared with patients without stroke, the risk of major adverse events was highest in the first three months after stroke (odds ratio 14) and appeared to level off after nine months. (See "Perioperative care of the surgical patient with neurologic disease", section on 'Patients with a history of stroke'.)

Antidepressants and risk of congenital cardiac defects (August 2014)

A large population-based study has provided reassuring results suggesting that treatment with antidepressants during pregnancy is not associated with congenital cardiac defects [63]. The study used an administrative claims database to compare infants of depressed mothers who were either treated with antidepressants during the first trimester or not treated with antidepressants. After adjusting for confounding, there was no significant difference in risk of congenital cardiac malformations among exposed versus unexposed infants. Seven other analyses examined specific exposure to selective serotonin reuptake inhibitors (as a class), fluoxetine, paroxetine, sertraline, serotonin-norepinephrine reuptake inhibitors, tricyclics, and bupropion; in each analysis, exposure was not associated with an increased risk of cardiac defects. (See "Risks of antidepressants during pregnancy", section on 'Antidepressant composite data'.)

Evaluation for occult atrial fibrillation in patients with cryptogenic stroke or TIA (June 2014)

Two recent trials confirm that paroxysmal atrial fibrillation (AF), an important potential mechanism for ischemic stroke, may be missed using standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors:

In the CRYSTAL AF trial, 441 patients with cryptogenic stroke and no evidence of AF during at least 24 hours of ECG monitoring were randomly assigned to prolonged ambulatory cardiac monitoring with a subcutaneous implantable loop recorder or to a control group with conventional follow-up [64]. At six months, AF detection was significantly higher in the implantable recorder group (8.9 versus 1.4 percent in the control group).

In the EMBRACE trial, 572 patients who had a cryptogenic stroke or TIA (and no evidence of AF on routine monitoring) were randomly assigned to additional ambulatory monitoring with a 30-day external loop recorder or a 24-hour Holter monitor [65]. The rate of AF detection was significantly greater in the group monitored for 30 days (16.1 versus 3.2 percent).

Given these findings, we now suggest ambulatory cardiac monitoring for several weeks for patients with a cryptogenic ischemic stroke or TIA. Such patients are characterized by brain ischemia not attributable to a definite source of cardioembolism, large artery atherosclerosis, or small artery disease despite an extensive vascular and cardiac evaluation, including no evidence of AF on standard 12-lead ECG and 24-hour cardiac monitoring. (See "Overview of the evaluation of stroke", section on 'Monitoring for occult atrial fibrillation'.)

Adjunctive olanzapine for maintenance treatment in patients with treatment-resistant depression (June 2014)

For patients with unipolar major depression who have failed multiple treatment regimens and then responded to and tolerated adjunctive second-generation antipsychotics, it is reasonable to continue the antipsychotic to prevent relapse. This approach is supported by a randomized trial in which 444 patients with treatment-resistant depression who responded to open-label acute and continuation therapy with fluoxetine plus olanzapine were randomly assigned to 27-weeks of maintenance therapy with fluoxetine plus olanzapine or fluoxetine monotherapy [66]. Patients who received adjunctive olanzapine had fewer recurrences (16 versus 32 percent). However, adjunctive olanzapine was associated with increased weight gain and adverse changes in glucose, triglycerides, cholesterol, and prolactin. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics", section on 'Maintenance phase'.)

ADULT RHEUMATOLOGY

Individually tailored hand exercise program for rheumatoid arthritis (October 2014)

An individualized hand exercise program involving stretching and strengthening may provide additional benefit to patients with rheumatoid arthritis (RA), even those on a stable regimen of disease-modifying antirheumatic drugs. In a randomized trial involving nearly 500 patients with RA, the addition of an individually tailored strengthening and stretching hand exercise program to usual care from a therapist resulted in significantly greater improvement in overall hand function at one year of follow-up compared with usual care alone [67]. (See "Nonpharmacologic and preventive therapies of rheumatoid arthritis", section on 'Occupational therapy'.)

Physical therapy may not benefit hip osteoarthritis (June 2014)

Physical therapy is typically recommended for management of hip osteoarthritis, despite limited evidence regarding its efficacy. In a sham-controlled randomized trial including over 100 patients with painful and radiographically-confirmed hip osteoarthritis, physical therapy (including a home exercise program) provided no benefit on pain and physical function as compared with placebo [68]. Although these findings question the utility of physical therapy for patients with hip osteoarthritis, additional studies are needed to better define the relative risks and benefits of different types of physical activity in the management of this disorder. (See "Nonpharmacologic therapy of osteoarthritis", section on 'Exercise'.)

Wine and increased risk of recurrent gout (June 2014)

Consumption of alcoholic beverages increases the risk of incident (new) and recurrent gout, although earlier data had suggested that beer and hard liquor increased the risk of incident gout, while wine may not. The risks of recurrent gout from alcohol intake were evaluated in an internet-based study including over 700 patients with established gout and at least one acute attack in the prior year; the patients served as their own controls [69]. A significant dose-response relationship was found between the amount of alcohol consumed from any of the three categories (beer, liquor, and wine) and the risk of recurrent gout flare during the subsequent 24 hours. Even moderate amounts of alcohol were associated with an increased risk during this period. The combinations of increased alcohol and high purine intake or diuretic use were associated with higher risk. (See "Prevention of recurrent gout", section on 'Alcohol'.)

GYNECOLOGY

Injectable progestins and risk of venous thrombosis (September 2014)

In contrast to other progestin-only contraceptives, depot medroxyprogesterone acetate (DMPA) use may be associated with an increased risk of venous thrombosis and embolism (VTE). In a case-control study, women with a first episode of VTE were twice as likely to be DMPA users than were controls in the general population [70]. In this study, VTE was not associated with use of progestin-only pills, the levonorgestrel-releasing intrauterine device, or the progestin-only contraceptive implant. However, in the absence of data about absolute risk of VTE in DMPA users, we continue to think that the advantages of using DMPA generally outweigh the risks for women with a history of VTE. (See "Depot medroxyprogesterone acetate for contraception", section on 'Cardiovascular risk'.)

Pelvic examination in asymptomatic women (July 2014)

Routine pelvic examinations in asymptomatic women are controversial. The American College of Physicians has issued guidelines that advise against performing screening pelvic examinations in asymptomatic, nonpregnant, adult women [71]. The American College of Obstetricians and Gynecologists continues to recommend annual pelvic examination for nonpregnant women age 21 years and older, but suggests that asymptomatic women participate in the decision [72]. We believe the decision whether or not to perform a complete pelvic examination at the time of the periodic health examination for the asymptomatic patient should be a shared decision after a discussion between the patient and her healthcare provider. (See "The gynecologic history and pelvic examination", section on 'Indications and frequency for examination'.)

OBSTETRICS

Low Apgar scores: Predictors of neonatal and infant deaths (November 2014)

Although not used to guide resuscitation, Apgar scores, first introduced in 1953, have been used as a measure of the newborn's overall clinical status and response to resuscitation during the first minutes after delivery. The accurate predictability of low Apgar scores for mortality was confirmed by a study that reviewed discharge and mortality data for all births in Scotland between 1992 and 2010 [73]. Linear regression analysis showed Apgar scores ≤3 at five minutes, compared with normal scores (between 7 and 10), were associated with 300-fold increased risk of early neonatal death (birth to seven days of life), 30-fold increased risk of late neonatal death (7 to 28 days of life), and 50-fold increased infant death (up to one year of age). (See "Neonatal resuscitation in the delivery room", section on 'Apgar scores'.)

Anticoagulation and placenta-mediated complications (October 2014)

Placenta-mediated pregnancy complications include pregnancy loss, severe/early-onset preeclampsia, and birth of small for gestational age infant. Anticoagulation has been recommended to prevent placenta-mediated pregnancy complications in women with thrombophilia, but the effectiveness of this approach is controversial. In a multinational randomized trial (TIPPS), prophylactic use of dalteparin in women with thrombophilia and a history of previous placenta-mediated pregnancy complications did not reduce the occurrence of the composite outcome (pregnancy loss, severe/early-onset preeclampsia, birth of small for gestational age infant, major venous thromboembolism) compared with women who did not receive dalteparin [74]. We believe the available evidence supports not prescribing anticoagulants to prevent adverse obstetrical outcomes in pregnant women with thrombophilia. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of pregnancy complications'.)

Aspirin for preventing preeclampsia (September 2014)

For women at high risk of developing preeclampsia, the US Preventive Services Task Force (USPSTF) now recommends use of low dose aspirin after 12 weeks of gestation to reduce the risk of preeclampsia, preterm birth, and fetal growth restriction [75]. Low dose aspirin prophylaxis results in potentially substantial benefit and no more than minimally harmful effects. This recommendation is consistent with recommendations of other professional organizations. The USPSTF also offered a pragmatic approach for selecting a high risk population, while acknowledging that there are no validated methods for identifying these women. (See "Preeclampsia: Prevention", section on 'Approach to therapy'.)

Physical activity reduces risk of type 2 diabetes after gestational diabetes (July 2014)

Increasing evidence suggests that an active lifestyle reduces the risk of developing type 2 diabetes in women with gestational diabetes. In a 16-year prospective observational study, 14 percent of women with a history of gestational diabetes self-reported the development of type 2 diabetes [76]. Women with a total physical activity level equivalent to 150 minutes per week of moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity had a 30 to 50 percent lower risk of developing type 2 diabetes than women with lower levels of physical activity. (See "Gestational diabetes mellitus: Glycemic control and maternal prognosis", section on 'Follow-up and prevention of type 2 diabetes'.)

Benefits of controlled cord traction (June 2014)

We suggest controlled cord traction to facilitate separation and delivery of the placenta. In a 2014 meta-analysis of randomized trials comparing controlled cord traction with a hands-off approach, controlled cord traction resulted in a 30 percent reduction in need for manual removal of the placenta, as well as small reductions in the duration of the third stage (three minutes), mean blood loss (10 mL), and incidence of postpartum hemorrhage (11.8 versus 12.7 percent); the rates of severe postpartum hemorrhage, need for additional uterotonics, and blood transfusion were similar [77]. Although the benefits of controlled cord traction are small, there are no significant harms from the maneuver if performed without excessive traction. (See "Management of normal labor and delivery", section on 'Delivery of the placenta'.)

Fish consumption advisory (June 2014)

Because of the potential fetal benefits of maternal docosahexaenoic acid (DHA) intake, the US Food and Drug Administration and the US Environmental Protection Agency now advise women who might become pregnant, pregnant women, and breastfeeding women to consume 8 to 12 ounces of a variety of fish lower in mercury each week (table 1), rather than "up to 12 ounces" as previously recommended [78]. This is consistent with two to three servings of fish per week. We suggest that pregnant and breastfeeding women try to achieve fish consumption resulting in at least 200 mg/day DHA intake instead of relying on the number of servings of fish, since fish vary widely in DHA content. (See "Fish consumption during pregnancy", section on 'Diet and supplements'.)

PEDIATRICS: GENERAL PEDIATRICS

Indications for voiding cystourethrogram after first UTI (December 2014)

Young children with urinary tract infection (UTI) often undergo imaging studies to evaluate for abnormalities such as vesicoureteral reflux (VUR). There is a lack of consensus about the optimal imaging strategy, particularly whether voiding cystourethrogram (VCUG) should be performed after the first UTI. Predictors of renal scarring after a first UTI were investigated in a meta-analysis of individual patient data from nine studies including >1200 children <18 years who underwent renal scintigraphy at least five months after their first UTI [79]. The risk of renal scarring was greatest in patients with Grade IV or V VUR (odds ratio 22.5); approximately two-thirds of children with scarring had either abnormal renal ultrasonography or the combination of temperature ≥39°C (102.2°F) and a pathogen other than Escherichia coli. Based on these findings, we have added the combination of temperature ≥39°C and a pathogen other than E. coli to our indications for obtaining a VCUG after a first febrile UTI. (See "Urinary tract infections in infants and children older than one month: Acute management, imaging, and prognosis", section on 'Indications'.)

Long-acting reversible contraception for adolescents (October 2014)

The intrauterine device and etonogestrel implant are two types of long-acting reversible contraception (LARC). Although LARC is more effective than other methods, few adolescents choose LARC. Lack of access to services, lack of information, and increased cost may be barriers to LARC for adolescents. Removal of these barriers appears to be associated with increased use of LARC and decreased rates of pregnancy. In a prospective study, 1404 urban adolescents 15 to 19 years of age were educated about reversible contraception (emphasizing the benefits of LARC), provided with their choice of reversible contraception at no cost, and followed for two to three years [80]. Nearly three-quarters of participants chose LARC. The pregnancy rate among participants was nearly five times less than that in a contemporaneous cohort of sexually active teenagers in the United States (34.0 versus 158.5 per 1000). The American Academy of Pediatrics now recommends the etonogestrel implant and intrauterine device as first-line contraceptive options for adolescents [81]. (See "Contraception: Overview of issues specific to adolescents", section on 'Overcoming barriers'.)

Weight gain after adenotonsillectomy for obstructive sleep apnea (October 2014)

Treatment of obstructive sleep apnea (OSA) by adenotonsillectomy may be associated with weight gain, at least in the short term. In a randomized trial, children with OSA treated with early adenotonsillectomy experienced more weight gain during the first seven months after surgery than those managed with watchful waiting [82]. Those who were overweight at baseline were more likely to become obese at follow-up if they were treated with adenotonsillectomy (52 versus 21 percent). Thus, when children who are at risk for overweight, overweight, or obese require adenotonsillectomy for treatment of OSA, care should be taken to minimize anticipated post-operative weight gain. (See "Management of obstructive sleep apnea in children", section on 'Adenotonsillectomy' and "Management of childhood obesity in the primary care setting", section on 'Prevention'.)

How to keep a cast dry (August 2014)

Keeping a cast dry can be challenging, but the various methods used to accomplish this are rarely studied. According to an observational laboratory study comparing six approaches, one effective and inexpensive method for maintaining a dry cast is to enclose the cast in two plastic bags, one over the other, and seal each bag to the skin with duct tape (picture 1) [83]. This approach was substantially more effective than using a single plastic bag sealed with either a rubber band or duct tape, and equally effective as expensive commercial products. (See "General principles of definitive fracture management", section on 'Complications'.)

Updated recommendations for palivizumab RSV prophylaxis (August 2014)

In 2014, the American Academy of Pediatrics updated its guidance for palivizumab prophylaxis for respiratory syncytial virus (RSV) infection [84]. Important changes include:

Palivizumab prophylaxis is no longer recommended for infants born at ≥29 weeks’ gestation unless they have additional risk factors for RSV (eg, chronic lung disease of prematurity [CLD]). 

Palivizumab prophylaxis is no longer recommended during the second year of life for infants with hemodynamically significant heart disease.

Continuation of palivizumab prophylaxis is no longer recommended for infants with breakthrough RSV infection.

Recommendations for infants with CLD are largely unchanged. (See "Respiratory syncytial virus infection: Prevention", section on 'Indications for palivizumab'.)

Discontinuation of daily desmopressin for nocturnal enuresis (August 2014)

Desmopressin is an effective therapy for children with nocturnal enuresis, but has a higher relapse rate than enuresis alarms. Tapering the dose before discontinuation may decrease relapse. In a multicenter randomized trial, relapse rates 12 weeks after discontinuation of desmopressin were lower in children whose dose was tapered (either by giving one-half the usual dose each day or by giving the usual dose every other day) for two weeks before discontinuation (39 and 42 percent, respectively) than in children who received a placebo (53 percent) or had desmopressin discontinued abruptly (55 percent) [85]. When daily desmopressin is discontinued, we suggest tapering rather than abrupt discontinuation. (See "Nocturnal enuresis in children: Management", section on 'Discontinuation'.)

Risk of traumatic brain injury in children with isolated scalp hematomas (August 2014)

Most children with isolated scalp hematomas and no other clinical symptoms do not have clinically important traumatic brain injury (ciTBI), but certain features may increase risk. In particular, hematomas can be an important indicator of potential TBI when they appear in younger infants. In a multicenter observational study of 2998 children younger than 24 months of age with an isolated scalp hematoma, ciTBI occurred in only 12 patients, none of whom died or required neurosurgery [86]. Of 111 patients younger than three months who underwent computed tomography, 21 percent had radiographic findings of TBI (eg, subdural or epidural hematomas, cerebral or subarachnoid hemorrhages, or cerebral contusions). A previously validated clinical score incorporates age, hematoma size, and hematoma location and may help stratify the risk of TBI in young infants (table 2). (See "Minor head trauma in infants and children: Evaluation", section on 'Common findings'.)

Pediatric health effects of public smoking bans (June 2014)

Policies that ban indoor smoking in workplaces and public places have been associated with long-term health benefits in adults. Smoking bans also appear to be associated with immediate health benefits in children. In a meta-analysis of quasi-experimental observational studies, public smoking bans were associated with reductions of approximately 10 percent in preterm births and hospital admissions for asthma [87]. Some of the effects may be mediated through home smoking bans, which often are prompted by public smoking bans. Additional studies are necessary to determine the effects of smoking bans on respiratory tract infections and other child-health outcomes. (See "Control of secondhand smoke exposure", section on 'Public smoking bans'.)

PEDIATRICS: DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS

Peer victimization (bullying) and suicide attempts (July 2014)

Suicide attempts in children and adolescents are common, and peer victimization (bullying) is one of several risk factors. A meta-analysis of nine studies including more than 70,000 children and adolescents found that suicide attempts were two to three times more likely to occur in children who were victimized than in those who were not  [88]. In addition, suicidal ideation was more strongly related to cyberbullying than traditional bullying. (See "Suicidal behavior in children and adolescents: Epidemiology and risk factors", section on 'Exposure to violence or victimization'.)

PEDIATRIC NEONATOLOGY

Transcutaneous bilirubin measurements after discontinuation of phototherapy in neonates (November 2014)

In neonates, transcutaneous bilirubin (TcB) measurement devices are used to estimate total serum or plasma bilirubin (TB), thereby reducing the need for blood sampling. While TcB measurements are typically lower than TB, the degree of underestimation is greater in infants with high TB levels (>15 mg/dL [257 micromol/L]), dark-skinned infants, and during phototherapy. In these settings, TB may be needed to accurately determine the magnitude of hyperbilirubinemia. A German study has also reported TcB underestimation of TB is greater within the first eight hours of discontinuation of phototherapy [89]. This difference between TcB and TB measurements subsequently decreases, and returns to pretreatment values 24 hours after discontinuation of phototherapy. As a result, clinicians must take into consideration the timing of TcB measurement in relationship to discontinuation of phototherapy. If there is any question regarding the validity of TcB measurements, TB should be obtained to assess the degree of neonatal hyperbilirubinemia. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Transcutaneous bilirubin'.)

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