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What's new in family medicine
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What's new in family medicine

Disclosures: David M Rind, MD Employee of UpToDate, Inc. Equity Ownership/Stock Options (Spouse): Bonfire Development Advisors [CBT (iCBT)]. H Nancy Sokol, MD Nothing to disclose. Lee Park, MD, MPH Employment (Spouse): Novartis [Age-related macular degeneration (ranibizumab)].

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2015. | This topic last updated: Apr 16, 2015.

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

Herbal products for treatment of insomnia (March 2015)

A variety of herbal products are purported to be useful for insomnia. There is little evidence from randomized controlled trials about the efficacy of many herbals, however, and for those that have been well studied (eg, valerian), there is little evidence of benefit. A meta-analysis of 14 randomized trials in over 1600 patients found no significant difference between any herbal medicine and placebo on any clinical insomnia outcome measure [1]. The majority of the trials (11 out of 14) studied valerian; chamomile, kava, and wuling were studied in one trial each. Unlike other herbals in the study, valerian was associated with a greater number of adverse events per person compared with placebo. (See "Treatment of insomnia", section on 'Over-the-counter'.)

Long duration of hot flashes (March 2015)

For many if not most menopausal women, hot flashes last considerably longer than the duration currently recommended for treatment of symptoms (maximum 4 to 5 years to minimize excess breast cancer risk). Among 1449 women with hot flashes followed longitudinally in the Study of Women Across the Nation (SWAN), the median total hot flash duration was 7.4 years, with symptoms persisting for a median of 4.5 years after the final menstrual period (FMP) [2]. Women who were premenopausal or early perimenopausal when they first experienced hot flashes had the longest total duration (>11.8 years, post-FMP median duration 9.4 years). The long duration of hot flashes raises important treatment challenges for many women, particularly those with early onset symptoms. (See "Menopausal hot flashes", section on 'Duration'.)

Revised name and diagnostic criteria for chronic fatigue syndrome (February 2015)

Diagnostic criteria for chronic fatigue syndrome have been revised (table 1) by the Institute of Medicine (IOM), which has also suggested renaming the condition as systemic exertion intolerance disease (SEID) [3]. The IOM diagnostic criteria focus on the most specific features of the disease. Symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least one-half of the time. Other criteria include post-exertional malaise, sleep problems, cognitive impairment, and orthostatic-related symptoms. (See "Clinical features and diagnosis of chronic fatigue syndrome (systemic exertion intolerance disease)", section on 'Definition'.)

Light-emitting e-readers delay normal circadian rhythms and interfere with sleep (February 2015)

Prolonged use of portable light-emitting devices (laptops, tablets, smartphones) before bedtime can have a negative impact on melatonin secretion, circadian rhythms, and sleep. One study compared the effects of reading an electronic book on a light-emitting device (LE-ebook) versus a printed book (by reflected light) for four hours prior to bedtime for five consecutive nights [4]. Subjects in the LE-ebook group had suppressed melatonin concentrations in the early part of the night, a delayed endogenous circadian melatonin phase, felt less sleepy before bed, took longer to fall asleep, and reported feeling sleepier the following morning. These observations suggest that evening use of light-emitting devices may contribute to phase-delays in the circadian clock and difficulty initiating sleep.  (See "Physiology and available preparations of melatonin", section on 'Effects of drugs or light'.)

Adverse consequences of opioid use in chronic pain (January 2015)

There is uncertainty that opioids have long-term effectiveness in the treatment of fibromyalgia or other chronic pain conditions, and risks of harm from chronic opioid therapy likely outweigh the benefits. The avoidance of opioids in patients with chronic pain is further supported by a 2015 systematic review of the effectiveness and risks of long-term opioid therapy for chronic pain [5]. The review showed evidence of a dose-dependent risk for a range of harms, such as overdose, opioid abuse, fractures, myocardial infarction, and sexual dysfunction, but found insufficient evidence from observational studies to determine the effectiveness of such therapy and no placebo-controlled trials that met inclusion criteria for the review. (See "Treatment of fibromyalgia in adults not responsive to initial therapies", section on 'Analgesics' and "Overview of the treatment of chronic pain".)

Antihypertensive therapy provides benefit in mild hypertension (January 2015)

The benefit of antihypertensive drug therapy has been questioned in patients with mild hypertension (systolic 140 to 159 mmHg and/or diastolic 90 to 99 mmHg) and no preexisting cardiovascular disease. A meta-analysis including 15,266 such patients reported that, compared with placebo or a less intensive regimen, antihypertensive therapy or a more intensive regimen for five years produced significantly lower rates of all-cause mortality (3.9 versus 4.8 percent) and stroke (1.6 versus 2.1 percent), and similar rates of myocardial infarction [6]. Thus, low-risk patients with mild hypertension and no preexisting cardiovascular disease who fail to reduce their blood pressure with lifestyle modification should receive antihypertensive therapy. (See "Hypertension: Who should be treated?", section on 'Low-risk patients'.)

Approval of the direct factor Xa inhibitor edoxaban (January 2015)

The US Food and Drug Administration has approved the oral direct factor Xa inhibitor edoxaban (Savaysa; Lixiana in Japan) for the prevention of stroke in nonvalvular atrial fibrillation and the treatment of venous thromboembolism, based upon earlier randomized trials demonstrating non-inferiority to warfarin [7-9]. Dosing is once daily at a fixed dose without monitoring. There are Boxed Warnings regarding avoidance of edoxaban in patients with atrial fibrillation who have a creatinine clearance >95 mL/minute, spinal/epidural hematoma in patients undergoing neuraxial procedures, and ischemic events following premature discontinuation. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Anticoagulation in acute pulmonary embolism" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Edoxaban'.)

Transobturator versus retropubic slings for stress urinary incontinence in women (December 2014)

Five-year follow-up data from the Trial of Midurethral Slings (TOMUS), which randomized women to either a retropubic sling or a transobturator sling, demonstrated decreasing continence rates for women in both treatment groups [10]. The continence rate was higher in retropubic sling patients as compared with transobturator sling patients, but not statistically different (51.3 percent versus 43.4 percent). A greater proportion of women who underwent a transobturator sling procedure reported a "much better or very much better" urinary status. The overall mesh erosion rate was low, but new mesh exposures developed remote from surgery. Both retropubic slings and transobturator slings are reasonable choices for the surgical management of stress urinary incontinence in women, but the continence rates of both procedures decrease with time. (See "Surgical management of stress urinary incontinence in women: Choosing a type of midurethral sling", section on 'Transobturator versus retropubic midurethral slings'.)

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 [11]. 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 [12], 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'.)

GERIATRICS

Home modifications to prevent falls (January 2015)

Fall prevention for community dwelling older adults has the potential to significantly improve quality of life and impact morbidity and mortality, but few fall prevention interventions have been shown to be effective. A cluster-randomized trial evaluated a standardized set of home safety interventions (installation of stair hand rails, grab rails in bathrooms, improved lighting, slip-resistant deck surfacing, non-slip bathmats, pamphlet on home safety), comparing injury-related insurance claims in households that were randomized to the intervention with those that were wait-listed [13]. Over a three year period, there was a 26 percent decrease in fall-related injuries in the intervention group compared to the control group. (See "Falls: Prevention in community-dwelling older persons", section on 'Environment/assistive technology'.)

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) [14].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'.)

PREVENTION

Statins and pregnancy (April 2015)

The safety of statins in pregnancy is uncertain, but animal studies have raised concerns about fetal harm; human data are mixed. A cohort study of women enrolled in the US Medicaid program found that an association between statins and malformations was no longer present after a propensity analysis that controlled for potential confounders; pre-existing diabetes appeared to be the most important confounder [15]. However, the wide confidence intervals in this study do not exclude a potential increase (or decrease) in risk with statin therapy. We continue to recommend that statins be discontinued prior to conception if possible. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)

Exercise and vitamin D for fall prevention in older women (March 2015)

A randomized trial in home-dwelling women aged 70 to 80 years old with a history of at least one fall in the previous year evaluated the effect of exercise and/or vitamin D supplementation (800 IU per day) on fall prevention [16]. Strength and balance training did not affect the rate of falls, but halved the number of injurious falls and injured fallers, and improved muscle strength and balance compared with no exercise. Vitamin D, compared with placebo, did not prevent falls or fall-related injuries. Baseline 25-hydroxyvitamin D levels in the trial participants (26 to 28 ng/mL) were above the threshold for what is generally considered deficient. Prior meta-analyses have inconsistent findings on the effectiveness of vitamin D in fall prevention. We continue to suggest an exercise program to improve strength and balance for older adults at risk for falls. Given the low risk associated with vitamin D supplementation, and the possibility of benefit at least in adults with low baseline levels of vitamin D, we also continue to advise vitamin D supplementation. (See "Falls: Prevention in community-dwelling older persons", section on 'Exercise' and "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation'.)

PCSK9 inhibitors to reduce LDL-cholesterol (March 2015)

Monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9) reduce LDL-cholesterol levels by as much as 70 percent. While many non-statin lipid lowering therapies have not demonstrated convincing clinical benefits, trials of two PCSK9 inhibitors (evolocumab and alirocumab) suggest that this class of medication may improve cardiovascular (CV) outcomes even in patients who are already on statin therapy. In two open-label trials that were combined for analysis, patients treated with evolocumab had a lower rate of CV events (1.0 versus 2.2 percent, hazard ratio [HR] 0.47) [17]. In a placebo-controlled trial, patients treated with alirocumab had a lower rate of a post hoc CV composite (1.7 versus 3.3 percent, HR 0.52); however, there was no statistically-significant reduction in the originally planned CV safety composite. Neurocognitive events, although uncommon, appear to occur with both these medications, and both require subcutaneous injection once or twice per month. PCSK9 inhibitors are not yet generally available, but may become an important class of medication for reducing CV risk. (See "Lipid lowering with drugs other than statins and fibrates", section on 'PCSK9 inhibitors'.)

Choice of influenza vaccine formulation in patients with egg allergy (March 2015)

Most influenza vaccines are produced in an egg-based system, which has been a concern in patients with egg allergy. A number of observational studies have shown that administration of injectable inactivated influenza vaccine (IIV) containing up to 0.7 mcg ovalbumin per 0.5 mL dose is safe in patients with egg allergy. Two new observational studies have demonstrated safe administration of the intranasal live attenuated influenza vaccine (LAIV) containing <0.24 mcg ovalbumin per 0.2 mL dose in patients with egg allergy [18,19]. Influenza vaccine ovalbumin content is shown in the table (table 2). About 40 percent of patients in these studies had a history of anaphylaxis to egg and around 60 to 70 percent had asthma.

Based upon these findings and accumulating unpublished clinical experience, we recommend that all patients with egg allergy ≥6 months of age, including those with a history of anaphylaxis, receive annual immunization with an influenza vaccine according to the indications for all other patients without egg allergy. We would administer any age-appropriate, approved influenza vaccine (table 2), including the LAIV, in these patients according to the indications and contraindications outlined in the tables (table 3 and table 4). The vaccine is administered in a single dose rather than in two or more doses as a graded challenge. A 30 minute observation period is still suggested for patients with egg allergy who receive an egg-based influenza vaccine. This observation period is not necessary for those receiving an egg-free influenza vaccine. (See "Influenza vaccination in individuals with egg allergy", section on 'Safety of vaccines in patients with egg allergy' and "Influenza vaccination in individuals with egg allergy", section on 'Our approach'.)

Pneumococcal conjugate vaccine in adults ≥65 years of age (September 2014, MODIFIED March 2015)

The CAPiTA trial, which is the largest trial to assess the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13) in adults, compared PCV13 to placebo in approximately 85,000 immunocompetent adults ≥65 years of age in the Netherlands who had not received a pneumococcal vaccine previously [20]. The trial demonstrated 46 percent efficacy of PCV13 against vaccine-type pneumococcal pneumonia, 45 percent efficacy against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy against vaccine-type invasive pneumococcal disease. Efficacy persisted for the duration of the trial (mean follow-up four years). 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 'Efficacy'.)

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 PCV13 for all adults ≥65 years of age [21]. The ACIP revision was prompted by results from the CAPiTA trial. 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. (See "Pneumococcal vaccination in adults", section on 'Indications'.)

Comparison among multivariate risk models to estimate 10-year CVD risk (February 2015)

A number of multivariate risk models have been developed for estimating the risk of cardiovascular disease (CVD) events in apparently healthy, asymptomatic individuals. The performance of five risk scores (1998 Framingham, 2002 ATP III, 2008 Framingham, Reynolds Risk Score, and 2013 AHA/ACC score) was evaluated by generating an estimated 10-year CVD risk within a racially-diverse population aged 50 to 74 years without baseline evidence of CVD or diabetes [22]. When comparing the predicted and observed rates of CVD over 10 years, four of the five risk scores significantly overestimated the 10-year CVD risk (between 25 and 115 percent), while the Reynolds Risk score slightly underestimated risk (3 percent underestimation). The potential for overestimation of risk should be recognized in the discussion of risk and the decision-making process regarding therapies aimed at primary prevention. (See "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'Comparison among different risk scores'.)

Varenicline for smokers who are not ready to be abstinent (February 2015)

Varenicline may be helpful for patients who smoke and who are not ready to commit to immediate cessation. A randomized trial compared varenicline with placebo for 24 weeks in 1510 smokers who were not planning to make a quit attempt within the next month but were willing to reduce smoking and attempt quitting within the next three months [23]. Compared with placebo, patients in the varenicline group had a higher continuous abstinence rate at 21 through 24 weeks and at 52 weeks. (See "Pharmacotherapy for smoking cessation in adults", section on 'Administration'.)

Impact of prolonged sedentary time (February 2015)

A 2015 systematic review and meta-analysis adds to the mounting evidence of the negative effects of prolonged sedentary time [24]. The review found that prolonged sedentary time was associated with increased risk for mortality, cardiovascular disease, diabetes, and cancer. The increased risks were not mitigated by participation in physical exercise, though the effects were more pronounced at lower levels of physical activity. (See "The benefits and risks of exercise", section on 'Physical inactivity and health'.)

Additional causes of smoking mortality (February 2015)

In addition to the well-established adverse effects of smoking, a study using pooled data from five large cohorts found that, compared with never smokers, current smokers had an increased risk of mortality from renal failure, intestinal ischemia, hypertensive heart disease, any infection, breast cancer, and prostate cancer [25]. The study also found an increased risk of mortality from respiratory illnesses in addition to those previously recognized (pneumonia, influenza, COPD, and pulmonary fibrosis). The risk of mortality decreased with increasing duration of smoking cessation. (See "Benefits and risks of smoking cessation", section on 'Other'.)

 

New human papillomavirus (HPV) vaccine targets nine HPV types (February 2015)

Infection with human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58 is implicated in approximately 90 percent of invasive cervical cancers. The US Food and Drug Administration has approved Gardasil 9, a 9-valent HPV vaccine that targets those seven HPV types in addition to the two types associated with genital warts (6 and 11), for the prevention of HPV-related disease [26]. In a trial that included approximately 14,000 females randomly assigned to receive the 9-valent or quadrivalent HPV vaccine, immune responses with the two vaccines were comparable for the HPV types targeted by both (6, 11, 16, and 18). Additionally, the 9-valent HPV vaccine was 97 percent effective for preventing precancerous and cancerous lesions of the cervix, vagina, and vulva associated with the other targeted HPV types (31, 33, 45, 52, and 58). Safety profiles were overall similar. We favor the 9-valent HPV vaccine for its broader HPV type coverage.

Routine immunization should be offered to boys and girls aged 11 to 12, but can be administered as early as nine years of age. Catch-up vaccination should be offered for males between the ages of 13 to 21 and females between 13 to 26 years who have not been previously vaccinated. Repeat vaccination with the 9-valent vaccine is likely not warranted for individuals who have completed a series with a different HPV vaccine.

(See "Recommendations for the use of human papillomavirus vaccines", section on 'Available vaccines'.)

Lower HMG CoA reductase activity increases risk of diabetes (January 2015)

A Mendelian randomization study found that decreased genetic HMG CoA reductase activity is associated with a higher risk of type 2 diabetes, such that at least some of the risk of diabetes seen with statin therapy appears to be due to its inhibition of HMG CoA reductase [27]. Since this inhibition is thought responsible for the primary efficacy of statin therapy, this finding means that any effective statin will probably increase the risk of diabetes [28]. (See "Statins: Actions, side effects, and administration", section on 'Diabetes mellitus'.)

Tamoxifen prevention in women at high risk of breast cancer (January 2015)

Women at an increased risk of breast cancer are often prescribed a five-year course of tamoxifen for cancer prevention, but whether the benefits of tamoxifen extend beyond the course of treatment has not been clear. A new study suggests that tamoxifen confers long-term breast cancer prevention beyond the initial five years of treatment [29]. The International Breast Cancer Intervention Study I (IBIS-1) assigned over 7000 high risk women to tamoxifen 20 mg daily or placebo for five years. With 16 years of follow-up, tamoxifen significantly reduced the risk of breast cancer, with risk extending beyond the first ten years of follow-up. The risk reduction was primarily seen for hormone receptor-positive breast cancer. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Tamoxifen'.)

SCREENING

Interim guidelines for cervical cancer screening with primary HPV testing (February 2015)

Interim guidelines from the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology are the first US guidelines to suggest primary human papillomavirus (HPV) testing as an option for cervical cancer screening in women starting at age 25 years (table 5) [30]. This option is provided based on a randomized trial comparing primary HPV testing with cytology (Pap test) or co-testing (Pap test and HPV testing) [31]. Among women ≥25 years, primary HPV testing was more sensitive for the detection of cervical intraepithelial neoplasia (CIN) 3 or greater. However, the study is limited by having only three years of follow-up, use of a surrogate outcome (CIN3 rather than cancer), and highly structured follow up protocols that may not be feasible in practice. Given these limitations, we continue to suggest that women age <30 years not be screened for cervical cancer with primary HPV testing. (See "Screening for cervical cancer", section on 'Primary HPV testing'.)

Breast cancer mortality differences by race may reflect tumor biology (February 2015)

Breast cancer incidence in the United States is slightly lower in black women than white women, but breast cancer mortality is higher in blacks. Greater breast cancer mortality among black women may be due to differences in screening, cancer treatment, tumor biology, or comorbidity. In an observational study, based on the SEER database, of nearly 375,000 women with invasive breast cancer followed for a median of 38 months, black women were less likely to be diagnosed with stage 1 disease, and those with small-sized tumors were more likely to die of breast cancer than white women, after adjustment for estrogen receptor status [32]. This adds to emerging evidence that greater breast cancer mortality among black women relates, at least in part, to intrinsic differences in breast tumor biology between black and white women. (See "Screening for breast cancer: Strategies and recommendations", section on 'Epidemiology'.)

Supplemental ultrasound screening for women with dense breasts and normal mammography (January 2015)

In the United States, multiple states have passed legislation that advises supplemental whole breast ultrasound screening for women with dense breast tissue on mammography. A modeling study estimated that, for women ages 50 to 74 with heterogeneously or extremely dense breasts and a negative mammogram, supplemental ultrasound screening would cost more than $100,000 per quality adjusted life year (QALY) gained, and thus would not meet generally accepted thresholds for cost-effectiveness [33]. Compared with mammography alone, for 1000 women screened biennially for 25 years, supplemental ultrasound was predicted to prevent 0.36 additional cancer deaths, and lead to an additional 354 biopsies. To date, there have been no randomized trials in average-risk women comparing mammography alone with combination ultrasound and mammography. (See "Breast imaging for cancer screening: Mammography and ultrasonography", section on 'As adjunct to mammography for screening'.)

ADULT CARDIOVASCULAR MEDICINE

Vorapaxar particularly beneficial in patients with recent MI and diabetes (April 2015)

Patients with diabetes and myocardial infarction (MI) are at high risk of subsequent cardiovascular events. The impact of vorapaxar, an antiplatelet agent, on these high-risk individuals was evaluated in a subgroup analysis of the TRA 2P-TIMI 50 trial, which had previously shown benefit with this agent in a broad group of patients with atherosclerotic cardiovascular disease treated with at least one other antiplatelet drug (aspirin or clopidogrel) [34]. Vorapaxar lowered the risk of cardiovascular events to a greater extent in patients with diabetes and a history of MI than those without diabetes. For patients with diabetes and a recent MI who cannot receive either ticagrelor or prasugrel (our preferred P2Y12 receptor blockers; used in combination with aspirin), and who are at low risk for bleeding, we suggest that vorapaxar be added to clopidogrel and aspirin. (See "Secondary prevention of cardiovascular disease", section on 'Vorapaxar'.)

Digoxin for rate control in patients with atrial fibrillation (March 2015)

Data conflict as to whether digoxin used for rate control in patients with atrial fibrillation (AF), compared with no digoxin use, is associated with worse outcomes. In a post-hoc analysis of 14,171 patients in a database from a randomized trial of anticoagulation in AF, digoxin use was associated with increased adjusted all-cause mortality [35]. The mechanism underlying this association is unknown but, if not due to confounding factors, might be linked to elevated serum digoxin concentrations. This would support a practice of monitoring levels periodically in patients treated with digoxin. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy", section on 'Digoxin'.)

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 [36]. 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 [37]. 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 [38]. 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 [39]. 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'.)

ADULT ENDOCRINOLOGY AND DIABETES

Menopausal hormone therapy and risk of ovarian cancer (March 2015)

There have been concerns that menopausal hormone therapy (MHT) may be associated with an increase in ovarian cancer risk, but data are conflicting. A meta-analysis of 52 epidemiologic studies including 21,488 postmenopausal women with ovarian cancer now suggests that there is a small excess risk of ovarian cancer with MHT [40]. While the relative risk of ovarian cancer was greater in ever-users than never-users of MHT (RR 1.14), the calculated absolute excess risk associated with MHT was very low: five years of MHT use in women ages 50 to 54 years would result in about one additional ovarian cancer case per 1000 users and one ovarian cancer death per 1700 users. Given these low absolute risks, we do not consider ovarian cancer to be a major consideration when deciding to take MHT for symptomatic relief. (See "Menopausal hormone therapy: Benefits and risks", section on 'Ovarian cancer'.)

Long-term effect of antihypertensive therapy in diabetic patients (October 2014, MODIFIED March 2015)

A randomized trial and a meta-analysis have evaluated the treatment of hypertension in patients with diabetes.

The ADVANCE trial randomly assigned 11,000 diabetic patients to a fixed combination of perindopril-indapamide or placebo for approximately four years. 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 [41]. 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 of the trial completion 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 lower among those in the treatment group. 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'.)

A meta-analysis of 40 trials examined the effect of antihypertensive therapy in 100,354 diabetic patients [42]. Follow-up ranged from six months to more than eight years, with most trials following patients for two years or longer. Compared with placebo, antihypertensive therapy reduced the rates of mortality, total cardiovascular disease, myocardial infarction, and stroke. For most outcomes, the benefit of antihypertensive therapy was limited to those whose initial systolic pressures were greater than 140 mmHg. The risk of stroke, but not other outcomes, was reduced by antihypertensive therapy in patients with lower initial systolic pressures. Some trials compared one antihypertensive drug with another. For most outcomes, no class of drugs was superior or inferior to the others. However, beta-blockers increased the risk of stroke compared with other agents. In general, the results of this meta-analysis support recommendations by UpToDate regarding the treatment of hypertension in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Meta-analysis'.)

Characterizing treatment-induced neuropathy of diabetes (January 2015)

Treatment-induced neuropathy of diabetes (TIND) is a small fiber neuropathy that can occur in patients with chronic hyperglycemia who experience rapid improvement in glycemic control. The main clinical manifestations are severe pain and autonomic dysfunction. Although historically considered rare, data from a study of 954 patients referred to a tertiary care center for diabetic neuropathy evaluation suggest that TIND is more common than previously suspected [43]. Defined by the acute onset of neuropathic pain or autonomic dysfunction within eight weeks of a large improvement in glycemic control (ie, a decrease in glycosylated hemoglobin A1C of ≥2 percentage points over three months), TIND was present in 104 patients (11 percent). The risk of developing TIND and the severity of neuropathic pain and autonomic dysfunction correlated with the magnitude of decrease in hemoglobin A1C. (See "Epidemiology and classification of diabetic neuropathy", section on 'Treatment-induced neuropathy of diabetes'.)

Glycemic control and mortality in type 1 diabetes mellitus (January 2015)

In a report from the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications Study (EDIC), representing a mean follow-up period of 27 years (1429 patients), there was a modest reduction in all-cause mortality in patients with type 1 diabetes initially assigned to intensive insulin therapy (43 deaths in the intensive therapy group versus 64 in the conventional group) [44]. The median A1C values for the intensive therapy and conventional therapy groups during the 6.5 year DCCT were 7.2 and 9.1 percent, respectively. However, the A1C levels equalized during the subsequent EDIC study. Thus, compared with conventional therapy, intensive insulin therapy for 6.5 years during the DCCT reduced the risk of mortality over at least the next 20 years, despite an absence of a difference in A1C values during the post-DCCT period. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Mortality'.)

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 [41]. 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 [45]. 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'.)

ADULT GASTROENTEROLOGY

Interferon-free regimens for chronic genotype 1 HCV infection (December 2013, MODIFIED January 2015)

Several highly effective and well tolerated interferon-free options are now available for chronic genotype 1 hepatitis C virus (HCV) infection. Ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir plus dasabuvir, and simeprevir plus sofosbuvir all achieve sustained virologic response (SVR) rates, and thus effective cure, in excess of 90 percent in genotype 1 infected patients [46-54]. The duration of the regimen and the decision of whether to add weight-based ribavirin depend on the treatment history, presence of cirrhosis, and, for the ombitasvir-paritaprevir-ritonavir plus dasabuvir regimen, the infecting subtype (1a or 1b) (algorithm 2). The choice between the regimens depends primarily on the potential for drug interactions and drug toxicity. Additionally, in the United States, options will be limited by the individual's insurance provider. If cost or insurance coverage is not an issue, we generally favor the regimen of ledipasvir-sofosbuvir for its favorable adverse effect profile, its minimal drug interactions, and its ease of administration (a single pill once daily). (See "Treatment regimens for chronic hepatitis C virus genotype 1", section on 'Selection of treatment regimens'.)

ADULT INFECTIOUS DISEASE

Circulating influenza A H3N2 viruses and influenza vaccine effectiveness in the United States (December 2014, MODIFIED March 2015)

In December 2014, the United States Centers for Disease Control and Prevention (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 [55]. Most isolated influenza viruses to date 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. In seasons where predominant circulating influenza viruses have antigenically drifted, decreased vaccine effectiveness has been observed. Nevertheless, vaccination typically provides some cross-protection against drifted viruses and should still reduce hospitalization and death. As of late February 2015, overall vaccine effectiveness was only 19 percent and vaccine effectiveness against influenza A H3N2 was only 18 percent [56]. Influenza vaccination is still highly recommended [55]. 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' and "Seasonal influenza in children: Prevention with vaccines", section on 'Drifted H3N2 viruses during the 2014 to 2015 influenza season'.)

Interferon-free regimens to treat HCV in HIV/HCV coinfected patients (February 2015)

Patients coinfected with HIV and hepatitis C virus (HCV) traditionally had lower response rates to HCV treatment with peginterferon and ribavirin compared with individuals without HIV infection. However, with the use of direct-acting antiviral (DAA) agents in HCV treatment, HIV infection is no longer a negative predictor of response. In two studies of HIV/HCV genotype 1 coinfected individuals, sustained virological response rates to two interferon-free DAA regimens (ledipasvir-sofosbuvir or ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin) were greater than 90 percent, comparable to rates in populations infected with HCV alone [57,58]. The major consideration in HCV antiviral regimen selection for HIV/HCV coinfected patients is the potential for drug interactions between antiretroviral and HCV antiviral agents. (See "Treatment of hepatitis C virus infection in the HIV-infected patient", section on 'Genotype 1 infection'.)

Pneumonia and long-term cardiovascular risk (February 2015)

Community-acquired pneumonia has been associated with increased short-term risk of cardiac events. In two cohorts of community-dwelling adults, hospitalization for pneumonia was also associated with increased long-term risk of new-onset cardiovascular disease (myocardial infarction, cerebrovascular accident, or fatal coronary heart disease), even after adjusting for traditional cardiovascular risk factors [59]. In one of the cohorts, the risk of cardiovascular events among patients with pneumonia was highest during the first year after hospitalization and remained higher than among controls through 10 years. In the other cohort, the risk of cardiovascular events was elevated during the first two years following pneumonia hospitalization, but not thereafter. (See "Prognosis of community-acquired pneumonia in adults", section on 'Association with cardiovascular events'.)

Oseltamivir for the treatment of influenza in adults (January 2015)

Oseltamivir has been demonstrated to shorten the duration of influenza symptoms and to reduce the duration of viral shedding. However, studies and meta-analyses have provided contradictory results regarding the effect of oseltamivir on influenza-related lower respiratory tract complications in healthy adults. A 2015 meta-analysis evaluated all manufacturer-sponsored randomized trials, published and unpublished, of oseltamivir for the treatment of influenza in adults [60]. Among those with documented influenza, oseltamivir reduced the time to alleviation of all symptoms (median time 98 versus 123 hours), reduced lower respiratory tract complications requiring antibiotics, and reduced hospital admissions for any cause compared with placebo. In contrast to an earlier meta-analysis that aggregated study results and did not demonstrate a benefit with regards to complications, this meta-analysis pooled individual patient data from the trials, which is generally considered a more rigorous method [61]. These results support our recommendations to use an antiviral agent such as oseltamivir in patients with confirmed or suspected influenza and severe illness or at high risk of complications. (See "Treatment of seasonal influenza in adults", section on 'Efficacy of oseltamivir'.)

Rapid nucleic acid amplification test for seasonal influenza (January 2015)

A rapid nucleic acid amplification test for influenza, the Alere i influenza A & B test, is available in several countries in Europe. In January 2015, the US Food and Drug Administration allowed use of the test in non-traditional laboratory sites, including physicians' offices, emergency rooms, health department clinics, and other healthcare facilities [62]. This test uses a nasal swab sample and provides results (reports influenza A or B, but not subtypes) in as few as 15 minutes. It is performed on a small proprietary machine. Nucleic acid amplification tests are generally more sensitive than antigen and immunofluorescence techniques, which most other rapid influenza tests utilize. (See "Diagnosis of seasonal influenza in adults", section on 'Nucleic acid tests' and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Approach to testing'.)

Intravenous peramivir for influenza (December 2014)

Peramivir was approved by the US Food and Drug Administration (FDA) in December 2014 for treating uncomplicated influenza infection in adults who have been ill for ≤2 days [63,64]. Peramivir is the first IV neuraminidase inhibitor to be approved by the FDA, although it has been in use in Japan and South Korea for several years. It is administered as a single intravenous dose of 600 mg. In a randomized trial, those who received peramivir had their influenza symptoms alleviated an average of 21 hours sooner and became afebrile approximately 12 hours sooner than those who received placebo. Patients who cannot receive zanamivir or oseltamivir (eg, those who cannot tolerate inhaled or enteral agents) should receive IV peramivir. Although the FDA has only approved IV peramivir for patients with uncomplicated influenza, we think it is also reasonable to use it for patients with severe influenza who cannot receive oral oseltamivir or inhaled zanamivir; in such patients, we would use either oseltamivir by a nasogastric tube or IV peramivir. (See "Treatment of seasonal influenza in adults", section on 'Efficacy of peramivir' and "Treatment of seasonal influenza in adults".)

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 [65]. 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'.)

ADULT NEUROLOGY AND PSYCHIATRY

Treatment of extracranial carotid or vertebral artery dissection (March 2015)

Antithrombotic therapy with either anticoagulation or antiplatelet drugs has long been used as treatment for ischemic stroke and transient ischemic attack (TIA) caused by cervical arterial dissection, but the two therapies had never been compared in a randomized trial. This situation changed with publication of the open-label, assessor-blind CADISS pilot trial, which enrolled 250 subjects with extracranial carotid or vertebral dissection and randomly assigned them to antiplatelet or anticoagulant treatment for three months [66,67]. At the end of this period, there was no significant difference between the two treatment groups; ipsilateral ischemic stroke occurred in 3 of 126 patients (2 percent) in the antiplatelet group and 1 of 124 patients (1 percent) in the anticoagulant group. There were no deaths in either group and one major bleeding event in the anticoagulation group.

Because of the low stroke rate and rarity of outcome events, the CADISS trial was not able to establish which treatment is superior. However, in the absence of a clear advantage for anticoagulation, most UpToDate authors now favor aspirin over anticoagulation for treating cervical artery dissection because it is less complicated to administer and generally safer. However, some experts prefer anticoagulation rather than aspirin in this setting. Antithrombotic treatment must be delayed until 24 hours after thrombolytic therapy but can be started immediately for patients who are not treated with thrombolytic therapy. (See "Spontaneous cerebral and cervical artery dissection: Treatment and prognosis", section on 'Antithrombotic therapy'.)

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 [68]. 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'.)

ADULT PULMONOLOGY

Warning about use of non-prescription asthma treatments (April 2015)

The US Food and Drug Administration (FDA) released a consumer warning about the potential health risks of over-the-counter (OTC) homeopathic products for asthma [69]. The efficacy and safety of OTC products are not evaluated by the FDA. In addition, there is evidence that some non-prescription therapies, such as racemic epinephrine inhaler (sold as Asthmanefrin) and systemic ephedrine (sold as Bronkaid and Primatene tablets), are less effective than standard therapies for asthma and have a higher rate of side effects. Thus, OTC products are not recommended for the routine care of asthma, particularly acute asthma symptoms. These warnings are an important reminder for clinicians to ask their patients about use of OTC products. (See "Asthma in children younger than 12 years: Rescue treatment for acute symptoms", section on 'Nonstandard therapies' and "Alternative and experimental agents for the treatment of asthma", section on 'Risks associated with inhaled epinephrine' and "Alternative and experimental agents for the treatment of asthma", section on 'Homeopathic agents' and "Homeopathy", section on 'Specific diseases'.)

Negative D-dimer does not predict recurrence risk in unprovoked VTE (January 2015)

Indefinite anticoagulation is preferred in patients with a first episode of unprovoked venous thromboembolism (VTE). The D-dimer assay has been proposed as a test to identify patients in whom anticoagulant therapy may be safely discontinued. However, a prospective study that measured the VTE recurrence rate in 319 patients with a first episode of unprovoked VTE who had two consecutive negative D-dimer levels does not support this indication for d-dimer testing [70]. The first level was drawn following completion of a standard course of anticoagulant therapy and the second after one month off anticoagulation. The two year recurrence rate was 7 percent per patient-year, with higher rates reported in men (10 percent per patient year) compared with women (5 percent per patient year). These rates are sufficiently high that they support the current recommendation of indefinite anticoagulation in this population; D-dimer measurements do not appear to be useful in identifying candidates for more limited treatment. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Elevated D-dimer'.)

ADULT RHEUMATOLOGY

Possible association of giant cell arteritis with varicella zoster virus (March 2015)

The etiology of giant cell arteritis (GCA) remains unknown, although various infectious causes have been considered as triggering events. One of the largest studies to evaluate the relationship between varicella zoster virus (VZV) and GCA included temporal artery (TA) biopsies from 82 pathologically-confirmed GCA patients and 13 TA biopsies from healthy controls [71]. VZV antigen was found in 74 percent of pathologically-confirmed GCA TAs versus 8 percent of normal TAs. The majority of biopsies showing GCA contained VZV antigen in skip areas that correlated with adjacent GCA pathology. However, direct pathogenetic evidence of a causal role of VZV in GCA is lacking. (See "Pathogenesis of giant cell (temporal) arteritis", section on 'Etiology and pathogenesis'.)

Relative efficacy of pharmacologic interventions for knee osteoarthritis (February 2015)

A large network meta-analysis of 137 trials involving over 33,000 patients with knee osteoarthritis (OA) compared the relative efficacy of available treatments for knee OA [72]. All treatments, except acetaminophen, showed a clinically significant improvement from baseline pain. Intraarticular (IA) hyaluronic acid was found to be superior to oral and IA placebo, acetaminophen, celecoxib, and naproxen but not to ibuprofen, diclofenac, or IA glucocorticoids for pain relief. There also appeared to be a relative effect of IA administration when compared with oral medications, which was driven by a large placebo effect of IA injections. These findings are limited by the short-term follow-up period of three months as well as the use of indirect comparisons. (See "Treatment of osteoarthritis resistant to initial pharmacologic therapy", section on 'Comparison with intraarticular glucocorticoids'.)

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 [73]. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on 'Occupational therapy'.)

OBSTETRICS

Iron supplementation in pregnancy (April 2015)

The total maternal iron requirement associated with pregnancy is about 1000 mg. For this reason, many clinicians prescribe a prenatal vitamin with iron for pregnant women. In a 2015 systematic review for the US Preventive Services Task Force, routine iron supplementation in pregnancy resulted in a 50 to 80 percent reduction in the frequency of iron deficiency anemia at term, but effects on other pregnancy outcomes were inconsistent [74]. We suggest prenatal vitamins with iron for pregnant women for prevention of maternal iron deficiency anemia. (See "Nutrition in pregnancy", section on 'Iron'.)

False positive Down syndrome screening tests (April 2015)

Noninvasive prenatal Down syndrome screening using cell free DNA results in lower false positive and false negative rates than conventional aneuploidy screening tests. In a recent study of Down syndrome screening in an unselected population including almost 16,000 women, the false positive rates of cell free DNA and conventional screening were 0.1 and 5 percent, respectively, and false negative rates were 0 and 21 percent, respectively [75]. False positive results can be due to factors such as maternal mosaicism, maternal tumors, maternal copy number variants, vanishing twins, confined placental mosaicism, or a failure of the complex bioinformatics necessary to generate a result [76-82]. Despite the low false positive rate with cell free DNA screening, confirmatory diagnostic testing (genetic amniocentesis or chorionic villus sampling) is mandatory after a screen positive result. (See "Noninvasive prenatal testing using cell-free nucleic acids in maternal blood", section on 'Trisomy 21, 18, 13'.)

Safety of inhaled long-acting beta agonist/glucocorticoid for asthma during pregnancy (February 2015)

An important clinical question for pregnant women with asthma is whether using a combination long-acting beta-agonist (LABA) plus inhaled glucocorticoid confers an increased risk for adverse fetal outcomes, compared with monotherapy using a higher dose of the inhaled glucocorticoid. In a study of 1302 pregnant women with asthma, the risk for a major congenital malformation was not increased when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid, or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid [83]. (See "Management of asthma during pregnancy", section on 'Long-acting beta-adrenergic agents'.)

Target diastolic blood pressure in pregnancy (February 2015)

In pregnant women with chronic (preexistent) or gestational hypertension, the effect of less-tight versus tight control of hypertension on pregnancy complications is unclear. A randomized trial that assigned pregnant women with gestational or chronic hypertension to diastolic blood pressure treatment targets of 85 or 100 mmHg reported similar maternal, fetal, and neonatal outcomes in both groups [84]. More women in the 100 mmHg target group developed severe hypertension, although this was not associated with an increase in transient ischemic attack or stroke. The trial was not powered to exclude a clinically important increase in fetal growth restriction in the 85 mmHg target group. For these reasons, we continue to suggest a diastolic pressure target of 90 to 100 mmHg for pregnant women with hypertension without end-organ damage. (See "Management of hypertension in pregnant and postpartum women", section on 'Blood pressure goal'.)

Timing of antiretroviral initiation during pregnancy (January 2015)

The risk of HIV transmission from an infected mother to her infant is proportional to the level of maternal viremia at delivery. Among women not already taking an antiretroviral regimen, viral suppression at delivery is more likely when a regimen is initiated earlier during gestation. In a large US cohort of antiretroviral-naïve HIV-infected women who initiated a combination antiretroviral regimen during pregnancy, a detectable viral load at delivery was documented in 13 percent overall, but in 24 percent of those who initiated the regimen during the third trimester [85]. This supports our recommendation to initiate antiretroviral therapy promptly in treatment-naïve pregnant women with advanced HIV disease or CD4 cell count th week of gestation for HIV-infected pregnant women with higher CD4 cell counts. (See "Use of antiretroviral medications in pregnant HIV-infected patients and their infants in resource-rich settings", section on 'When to initiate antiretroviral medications during pregnancy'.)

No change to recommendations for pain medicine use in pregnancy (January 2015)

Studies of pain medicine use by pregnant women have suggested associations between prescription nonsteroidal antiinflammatory drugs (NSAIDs) and the risk of miscarriage, the use of acetaminophen and subsequent childhood attention deficit hyperactivity disorder (ADHD), and the use of opioids and the development of fetal neural tube defects. A 2015 US Food and Drug Administration (FDA) Drug Safety Communication has found methodologic limitations to these studies and inconclusive results regarding NSAIDs and acetaminophen use [86]. Further investigation is needed regarding maternal opioid use and the risk of fetal neural tube defects. It is always advisable for pregnant women to avoid medications that are not clearly needed. However, specific recommendations regarding analgesic use need not change based on this current analysis. (See "Initial prenatal assessment and first trimester prenatal care", section on 'Treatment of pain and fever'.)

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 [87]. 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'.)

PEDIATRICS: GENERAL PEDIATRICS

Early introduction of peanuts in high-risk infants (March 2015)

Previous guidelines recommended delayed introduction of highly allergenic solid foods (eg, eggs, peanuts, tree nuts, dairy products other than cow's milk, fish, and shellfish) for the purpose of preventing allergic disease in high-risk infants. However, evidence from observational studies suggested this practice was not effective and may lead to an increased incidence of food allergies. The Learning Early about Peanut Allergy (LEAP) trial is the first randomized trial to show benefit of early introduction of a major food allergen [88]. In this study, introduction of peanut at 4 to 11 months of age rather than avoidance until 60 months of age in children at high risk for peanut allergy due to severe eczema and/or egg allergy decreased the risk of developing peanut allergy. The rate of peanut allergy in the consumption group compared with the avoidance group was 1.9 versus 13.7 percent in children who were skin prick test-negative, and 10.6 versus 35.3 percent in children who were skin prick test-positive (wheal 1 to 4 mm). Exclusion criteria included a skin prick test wheal >4 mm or a positive baseline oral food challenge to peanut. These findings indicate that past recommendations to delay introduction of highly allergenic foods were appropriately rescinded. (See "Introducing formula and solid foods to infants at risk for allergic disease", section on 'Introduction of solid foods to high-risk infants'.)

National and ethnic variability in head circumference standards (March 2015)

The World Health Organization (WHO) Child Growth Standards were developed with data from the WHO Multicenter Growth Reference Study (MGRS) to describe normal growth in children younger than five years of age. However, it may be inappropriate to use a single head circumference standard for children from different countries or ethnic groups. A systematic review compared the mean head circumferences from the WHO MGRS with the mean head circumferences from a variety of studies in 55 countries or ethnic groups [89]. The mean head circumferences in some groups were sufficiently different from those of the MGRS that use of the WHO growth standards would result in misclassification of microcephaly or macrocephaly. When available, local head circumference standards may be preferable to the WHO growth standards. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Head circumference charts' and "Macrocephaly in infants and children: Etiology and evaluation", section on 'Head circumference charts'.)

Azithromycin and infantile pyloric stenosis (March 2015)

Treatment with erythromycin during the first few weeks of life is an established risk factor for developing infantile hypertrophic pyloric stenosis (IHPS). A large study further defines the magnitude of that risk, and reveals that azithromycin also is a risk factor for IHPS. In a retrospective cohort of more than one million infants, the risk of developing IHPS was increased more than ten-fold for exposure to erythromycin or azithromycin during the first two weeks of life, and more than three-fold for exposure between two and six weeks of age [90]. Exposure after six weeks of age was not associated with IHPS risk. (See "Infantile hypertrophic pyloric stenosis", section on 'Macrolide antibiotics'.)

Morphine is not more effective than ibuprofen for post-tonsillectomy pain in children (March 2015)

There is growing evidence that opioid medication should not be used as first-line analgesic therapy for post-tonsillectomy pain, particularly in children with underlying obstructive sleep apnea (OSA). A randomized trial found ibuprofen and acetaminophen to be as effective as morphine and acetaminophen for postoperative pain management in children undergoing tonsillectomy for OSA [91]. In addition, children treated with morphine had increased episodes of postoperative desaturation compared with baseline, whereas those who received ibuprofen had improvement in oxygen saturation postoperatively. Caution should be used in prescribing opioids post-tonsillectomy in patients with underlying OSA. (See "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications", section on 'Pain'.)

Strict cognitive rest associated with more symptoms in children with concussions (February 2015)

Strict cognitive rest, including avoidance of reading, video games, loud music, and screen time (computer, tablet, television, or smart phone), limitation of social activities, and absence from school, has been advocated as a primary treatment for pediatric concussion. However, evidence for this approach is sparse. In a trial of 99 patients aged 11 to 22 years who were diagnosed with a concussion after pediatric emergency department evaluation (36 percent with loss of consciousness), all subjects reduced physical activity and one group was assigned to strict cognitive rest for five days while the other was assigned to usual care (one to two days of rest followed by gradual return to full cognitive activities) [92]. Strict cognitive rest was associated with significantly more daily reported postconcussive symptoms during the 10 days of follow-up, while there were no differences in neurocognitive function or balance outcomes at three and 10 days after injury. Thus, strict cognitive rest was harmful in this trial. We suggest an individualized approach to cognitive rest, in which patients are instructed to avoid mental activities that worsen symptoms and are followed closely by a clinician with expertise in managing concussions. (See "Concussion in children and adolescents: Management", section on 'Cognitive rest'.)

Oat cereal for thickening infant bottle feeds (February 2015)

For healthy infants with problematic gastroesophageal reflux who are bottle-fed, thickening feeds with infant cereal slightly improves symptoms. Although rice cereal has traditionally been used for this purpose, oat cereal is now preferred because of concerns about possible contamination of rice cereal with arsenic [93-95]. The US Food and Drug Administration (FDA) is investigating to determine if there are clinically significant traces of arsenic in rice cereal. (See "Gastroesophageal reflux in infants", section on 'Thickening feeds'.)

Bronchodilators not routinely recommended for bronchiolitis in infants and children (January 2015)

In November 2014, the American Academy of Pediatrics released updated guidelines for the diagnosis, management, and prevention of bronchiolitis [96]. The 2014 guideline recommends against the administration of inhaled albuterol or epinephrine in the treatment of bronchiolitis; the previous guideline (2006) included a trial of bronchodilators as an option. We agree that bronchodilators should not be used routinely in the treatment of bronchiolitis and no longer suggest a trial of bronchodilators. Although bronchodilators may provide modest short-term clinical improvement, they do not affect overall outcome, may have adverse effects, and increase the cost of care.

While we no longer routinely suggest inhaled bronchodilators for infants and children with bronchiolitis, a one-time trial of inhaled bronchodilators may be warranted for infants and children with bronchiolitis and severe disease (eg, nasal flaring; retractions; grunting; respiratory rate >70 breaths per minute; dyspnea; or cyanosis) or respiratory failure. (See "Bronchiolitis in infants and children: Treatment; outcome; and prevention", section on 'Inhaled bronchodilators'.)

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 [97]. 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 Grade IV or V VUR 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 [98]. 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 [99]. (See "Contraception: Overview of issues specific to adolescents", section on 'Overcoming barriers'.)

PEDIATRICS: DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS

Sleep problems in children with ADHD (March 2015)

Attention deficit hyperactivity disorder (ADHD) is associated with sleep problems, particularly initiating and maintaining sleep. A randomized trial suggests that ADHD symptoms improve with treatment of comorbid sleep problems [100]. Children with ADHD and a moderate to severe sleep disorder were assigned to usual care or two sleep consultations and a follow-up phone call with a trained clinician; most of the children were receiving ADHD medications (predominantly methylphenidate). At the three- and six-month follow-up, children in the intervention group had modest improvements in ADHD symptoms and teacher-reported behavior. These findings highlight the importance of treating coexisting sleep problems in children with ADHD. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Treatment of coexisting conditions'.)

PEDIATRIC NEONATOLOGY

Early follow-up for newborns with short birth hospitalizations (March 2015)

In the United States (US) and other developed countries, a follow-up visit within 48 hours of discharge has been recommended for newborns with birth hospitalizations that are less than 48 hours. Support for an early follow-up visit was provided by a recent study using data from a large healthcare system in the US that showed early follow-up visits (within 72 hours of discharge) reduced the rate of rehospitalizations compared with later visits [101]. As a result, we recommend an early follow-up visit (in the home or the office/clinic) for newborn infants with a birth hospitalization that is less than 48 hours. (See "Overview of the routine management of the healthy newborn infant", section on 'Follow-up visit'.)

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 [102]. 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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