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What's new in family medicine
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What's new in family medicine
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2016. | This topic last updated: Aug 23, 2016.

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

Clinical manifestations of severe synthetic cannabinoid toxicity (July 2016)

Synthetic cannabinoids consist of a heterogeneous group of chemical compounds that act as agonists at cannabinoid receptors with 2 to 800 times the potency of delta-9 tetrahydrocannabinol (THC), the active component of cannabis (marijuana). They have emerged as a popular recreational drug in the United States and Europe. In an observational study of a multicenter, hospital-based registry of medical toxicology consultations, over two-thirds of 277 patients with single-agent exposure to synthetic cannabinoids had altered mental status including severe agitation, toxic psychosis, hallucinations, seizures, and coma [1]. Rhabdomyolysis and acute kidney injury were present in approximately 5 percent of these patients. There were three deaths, including a 17-year-old adolescent with sudden death after first-time inhalational use. Thus, unlike cannabis, synthetic cannabinoids have significant potential to cause serious and life-threatening toxicity among recreational users. (See "Synthetic cannabinoids: Acute intoxication", section on 'Clinical manifestations'.)

Endocrine Society publishes updated guidelines for primary aldosteronism (June 2016)

In 2016, the Endocrine Society updated their 2008 clinical practice guidelines for the diagnosis and treatment of primary aldosteronism [2]. They continue to recommend case detection and case confirmation in patient groups with a relatively high prevalence of primary aldosteronism (eg, hypertension with hypokalemia, adrenal incidentaloma, or family history early-onset hypertension). However, there are broadened indications for screening to include patients with sustained blood pressure >150 mmHg (systolic) and >100 mmHg (diastolic), and patients with hypertension and sleep apnea. In addition, they emphasize the need for more timely diagnosis and treatment of primary aldosteronism given its prevalence (10 percent in patients with hypertension) and its association with cardiovascular and renal damage. (See "Diagnosis of primary aldosteronism", section on 'Expert guidelines'.)

Mediterranean compared with low-fat or low-carbohydrate diet for weight loss (May 2016)

The impact of specific dietary composition on weight change remains uncertain. In a systematic review of five trials with follow-up ≥12 months, a Mediterranean diet resulted in similar weight loss (-4.1 to -10.1 kg) as a low-carbohydrate diet (-4.7 to -7.7 kg) and greater weight loss than a low-fat diet (2.9 to -5 kg) [3]. There was a similar reduction in lipid levels among the diets studied. The degree of adherence to the diet, irrespective of the particular macronutrient composition, is an important determinant of weight loss. We suggest choosing a diet or eating plan based upon patient preferences, which may improve long-term adherence. The diet should emphasize reductions in refined carbohydrates, processed meats, foods high in sodium and trans fat and higher intakes of fruits, nuts, fish, vegetables, and whole grains. (See "Obesity in adults: Dietary therapy", section on 'Weight loss diets'.)

Risks of oral ketoconazole for fungal skin and nail infections (May 2016)

In 2013, the US Food and Drug Administration (FDA) approved label changes for oral ketoconazole tablets to remove the indications for fungal skin and nail infections because of serious risks of oral ketoconazole treatment (serious liver damage, adrenal gland problems, and harmful drug interactions). In May 2016, based upon an FDA safety review that found continued prescribing of oral ketoconazole for fungal skin and nail infections (including one treatment-related patient death), the FDA released a drug safety communication warning healthcare professionals to avoid prescribing oral ketoconazole for skin and nail infections [4]. The risks of oral ketoconazole treatment for these indications outweigh the benefits. (See "Tinea versicolor (Pityriasis versicolor)", section on 'Other therapies'.)

Clinical practice guideline for chronic insomnia in adults (May 2016)

The American College of Physicians has released a new clinical practice guideline for the management of chronic insomnia in adults [5]. The guideline recommends that all patients receive cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder. The guideline suggests that clinicians use a shared decision-making approach, including discussion of benefits, harms, and costs of short-term use of medications, to decide whether to add medication to CBT-I in patients with persistent symptoms. This approach is consistent with our preference for behavioral therapy over medication in most patients with chronic insomnia, particularly in older adults and patients with organ dysfunction, who are at increased risk for side effects from sedative-hypnotic drugs. (See "Treatment of insomnia", section on 'General approach'.)

New guidelines for the management of acne vulgaris (May 2016)

The American Academy of Dermatology released new guidelines of care for the management of acne vulgaris in adolescents and adults [6]. The guidelines reviewed efficacy, regimens, and side effects of acne therapies and included an updated treatment algorithm for acne vulgaris. Specific areas covered by the guidelines include indications for evaluating patients for androgen excess, the role of topical antimicrobial and topical retinoid preparations, effective combination therapies, and optimal use of systemic antibiotics, hormonal therapies, and oral isotretinoin. (See "Treatment of acne vulgaris", section on 'General approach'.)

Updated guidelines for the treatment of venous thromboembolism (March 2016)

The American College of Chest Physicians (ACCP) has published new guidelines on antithrombotic therapy for venous thromboembolic (VTE) disease that include guidance on choice of anticoagulant, indications for extended anticoagulation, and indications for thrombolytic therapy in patients with acute pulmonary embolism (PE) [7]. In addition to a preference for direct oral anticoagulants for the treatment of VTE, the ACCP suggests extending anticoagulation beyond three months (ie, no scheduled stop date) in patients with unprovoked VTE or active cancer. For most patients with small subsegmental pulmonary embolism (SSPE), anticoagulation is suggested; however, clinical surveillance with lower extremity Doppler ultrasound may be appropriate for select patients with a low burden of SSPE who have no evidence of thrombus elsewhere and in whom the risk of recurrence is low. The guidelines suggest administration of systemic thrombolytic therapy, rather than catheter-directed thrombolysis (CDT), for patients with hemodynamically-significant PE; CDT may be appropriate for those who fail systemic thrombolysis or who are at high risk of bleeding. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Indications' and "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Patients likely to benefit' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients with subsegmental PE'.)

Agent selection for anticoagulation in venous thromboembolism (March 2016)

Guidelines for the treatment of acute venous thromboembolism (VTE) were issued by The American College of Chest Physicians (ACCP) [7]. Compared with earlier versions of the guidelines, the direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban, or dabigatran are now the preferred agents for long-term anticoagulation in patients who are not pregnant and do not have active cancer or severe renal insufficiency. This preference was based upon randomized trials that consistently reported similar efficacy, a lower bleeding risk, and improved convenience when compared with warfarin. We agree with this preference for DOACs in patients with acute VTE, understanding that choosing among anticoagulants frequently depends upon availability and cost as well as patient comorbidities and preferences. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)

Systemic exertion intolerance disease and association with suicide (March 2016)

The short-term prognosis for recovery of function is generally poor in systemic exertion intolerance disease (SEID), also known as chronic fatigue syndrome (CFS). The long-term prognosis may be better, although studies have been conflicting. SEID/CFS has not been associated with an increased risk of all-cause mortality but may be associated with an increased risk for suicide [8]. (See "Treatment of systemic exertion intolerance disease (chronic fatigue syndrome)", section on 'Prognosis'.)

GERIATRICS

Proton pump inhibitors and risk of dementia in older adults (February 2016)

A new study has identified a possible link between proton pump inhibitors (PPIs) and risk of dementia in older adults. In a prospective cohort study of >73,000 adults aged 75 years and older who were free of dementia at baseline, regular use of a PPI was associated with a 1.4-fold increase in the risk of incident dementia, independent of age, gender, depression, stroke, heart disease, and polypharmacy [9]. Possible factors that could contribute to this finding include PPI-induced vitamin B12 deficiency or an interaction between PPIs and amyloid beta deposition, although these factors were not examined in this study. On the other hand, the association may reflect residual confounding by factors related to both use of PPIs and the development of dementia, and more studies are needed to confirm or refute this association. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Medications'.)

PREVENTION

Inactivated influenza vaccine for 2016-2017 season in the northern hemisphere (August 2016)

The effectiveness of seasonal influenza vaccines varies from season to season and is determined by a number of factors, including the match between circulating influenza strains and influenza strains in the vaccine. During the 2015-2016 influenza season, data from the United States Influenza Vaccine Effectiveness Network indicated that inactivated influenza vaccine (IIV) was 63 percent effective in preventing influenza in children, but live attenuated influenza vaccine (LAIV) was not effective [10]. Findings of poor or lower than expected LAIV effectiveness were also noted during the 2013-2014 and 2014-2015 seasons in the United States. These findings are inconsistent with studies sponsored by the manufacturer and studies from other countries that found LAIV was effective (ranging from 46 to 58 percent) during the 2015-2016 season [11-14]; however, LAIV was less effective than IIV in all of these studies [15]. In June 2016, the United States Advisory Committee on Immunization Practices (ACIP) voted to recommend that LAIV not be used during the 2016-2017 influenza season; this recommendation must be approved by the United States Centers for Disease Control and Prevention (CDC) director before it becomes CDC policy [10]. While some countries have elected to continue using LAIV [11], we suggest IIV rather than LAIV for the 2016-2017 influenza season in the northern hemisphere. (See "Seasonal influenza in children: Prevention with vaccines", section on 'IIV versus LAIV' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation'.)

Abrupt smoking cessation compared with gradual smoking reduction (June 2016)

Earlier evidence from randomized trials had suggested that, after a quit date is set, abstinence rates were equivalent for patients who reduced smoking prior to the quit date or stopped smoking abruptly on the quit date. However, more recent studies suggest that among smokers who plan to quit in the near future, quit rates are higher for patients who stop abruptly. The most recent randomized trial included 697 smokers in England and found that gradual smoking cessation (decreasing by 75 percent in the two weeks prior to quitting) was associated with decreased likelihood of abstinence at four weeks when compared with abrupt smoking cessation (39 versus 49 percent) [16]. (See "Overview of smoking cessation management in adults", section on 'Setting a quit date'.)

Fruit and vegetable consumption and cardiovascular outcomes in China (April 2016)

Studies suggest that fruit and vegetable consumption is associated with a lower risk of coronary heart disease and stroke, but most of these studies had been conducted in Western Caucasian populations. A prospective cohort study of over 450,000 adults aged 30 to 79 years in China found that compared with little or no fresh fruit consumption, those who ate fresh fruit daily had decreased risk for cardiovascular death (hazard ratio [HR] 0.6), major coronary events (HR 0.66), ischemic stroke (HR 0.75), and hemorrhage stroke (HR 0.64) [17]. There was a dose-response relationship between each outcome and the amount of fresh fruit consumed. Additionally, fresh fruit consumption was associated with decreased blood pressure and blood glucose levels. (See "Healthy diet in adults", section on 'Cardiovascular disease'.)

SCREENING

USPSTF recommendations for skin cancer screening (August 2016)

In July 2016, the United States Preventive Services Task Force (USPSTF) updated its statement on skin cancer screening and concluded that there is insufficient evidence to assess the balance of benefits and harms of screening for skin cancer in asymptomatic adults with a clinical visual skin examination [18]. Although we agree with the USPSTF conclusion, we suggest that persons at higher risk for fatal melanoma (eg, white men 50 years of age and over), individuals with multiple moles or at least a few clinically atypical moles, and individuals with the “red hair phenotype” have a total body skin examination performed by a clinician who has had appropriate training in the identification of melanoma. (See "Screening and early detection of melanoma", section on 'Recommendations of expert groups'.)

USPSTF recommendations for colorectal cancer screening (July 2016)

The United States Preventive Services Task Force (USPSTF) issued new guidelines for colorectal cancer screening in average risk adults [19]. The guidelines make a strong recommendation for screening, starting at age 50 years and continuing to age 75 for most patients, but in a departure from prior recommendations do not give preference for any one of seven screening test strategies over another. Options for screening are shown in a table. We agree with this screening test strategy based on shared decision making. Incorporating patient personal preferences may increase the likelihood that ongoing screening will occur. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'USPSTF guidelines'.)

Blood test for colorectal cancer screening (April 2016)

In 2016, the US Food and Drug Administration (FDA) approved a second-generation plasma assay for the detection of circulating methylated Septin 9 (Epi proColon 2.0) for colorectal cancer screening [20]. This test detects Septin 9 DNA, which is hypermethylated in colorectal cancer but not in normal colon tissue. The test is intended for average-risk patients who refuse screening by guideline-recommended methods (eg, colonoscopy, sigmoidoscopy, fecal occult blood, or fecal DNA testing). A positive blood test should be followed up with a colonoscopy. However, there is no strong evidence of the effectiveness of screening for colorectal cancer with available plasma or serum markers. Until further evidence is available, we do not recommend blood tests for colorectal cancer screening. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Blood-based markers'.)

Screening for ovarian cancer in average risk women (March 2016)

The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest randomized trial evaluating the use of serum testing for CA 125 and transvaginal ultrasound (TVUS) for ovarian cancer screening in average risk women [21]. The trial compared three arms: no screening; screening with annual transvaginal ultrasound; and multimodal screening (MMS, consisting of annual CA 125 testing, followed by TVUS if the CA 125 was abnormal, using an algorithmic guideline). After a median of 11 years, cancers were detected in 0.7 percent of women in the MMS group and 0.6 percent of women in the control and TVUS-only groups. Compared with no screening, MMS detected cancer at an earlier stage and the primary analysis showed a nonsignificant trend toward a 15 percent reduction (95% CI -3 to 30) in mortality from ovarian cancer for MMS. When prevalent ovarian cancer cases were excluded, the mortality reduction with MMS was significant. The results of the UKCTOCS trial are not consistent with results from another randomized trial that did not show decreased mortality with MMS. Based on the available data, it is not clear that the benefits of screening for ovarian cancer outweigh the harms related to the adverse effects associated with false positive findings. UpToDate suggests not screening average risk women for ovarian cancer. (See "Screening for ovarian cancer", section on 'Multimodal screening'.)

ADULT CARDIOVASCULAR MEDICINE

Beta blocker therapy in patients with atrial fibrillation and heart failure (April 2016)

Randomized trials have shown that beta blocker therapy reduces mortality in patients with heart failure with reduced ejection fraction, but the effect of beta blocker therapy on prognosis in patients with atrial fibrillation and heart failure is uncertain. A meta-analysis that included 3066 patients with atrial fibrillation and heart failure found no reduction in mortality in this subgroup of patients, in contrast to the reduction in mortality seen in patients in sinus rhythm with heart failure. However, a subsequent observational study that included nearly 40,000 patients with atrial fibrillation and heart failure found that beta blocker therapy was associated with reduced mortality in this population [22]. Although a survival benefit from beta blocker therapy in patients with atrial fibrillation and heart failure with reduced ejection fraction has not been definitively established, beta blockers continue to serve as a primary therapy for rate control in these patients given their efficacy for rate control and the limitations of alternative therapies. (See "Use of beta blockers in heart failure with reduced ejection fraction".)

ADULT ENDOCRINOLOGY AND DIABETES

Microvascular outcomes with empagliflozin in patients with type 2 diabetes (July 2016)

There are few trials evaluating microvascular outcomes in patients taking sodium-glucose co-transporter 2 (SGLT2) inhibitors. Microvascular disease was a prespecified secondary outcome in a recent trial designed specifically to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease (CVD) [23]. In this trial, 7028 patients with type 2 diabetes and established CVD were randomly assigned to empagliflozin or placebo once daily; the majority of patients were also taking metformin, antihypertensives, and lipid-lowering agents. Incident or worsening nephropathy occurred in 12.7 and 18.8 percent of patients in the empagliflozin and placebo groups, respectively. The reduction in nephropathy drove the improved composite microvascular endpoint (the initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy) for empagliflozin. The mechanism behind the reduction in incident or worsening nephropathy with empagliflozin is likely multifactorial, but is thought to be largely related to a direct renovascular effect of empagliflozin. Whether other SGLT2 inhibitors have similar renal effects is unknown. There have been reports of acute kidney injury, some requiring hospitalization and dialysis, in patients taking canagliflozin or dapagliflozin. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)

Liraglutide and cardiovascular outcomes (June 2016)

Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control. However, there are few studies assessing clinically important cardiovascular health outcomes. In one such trial, 9340 patients with type 2 diabetes (mean A1C 8.7 percent) and underlying cardiovascular disease (prior myocardial infarction or stroke) or risk factors, were randomly assigned to liraglutide or placebo [24]. Many patients were taking metformin (76 percent), sulfonylureas (50 percent), and/or insulin (44 percent). After a median follow-up of 3.8 years, the primary endpoint (time to first occurrence of a composite endpoint [death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke]) occurred in fewer patients in the liraglutide group (13 versus 14.9 percent). The choice of additional therapy in metformin-treated patients with type 2 diabetes and persistent hyperglycemia should be individualized based upon patient characteristics, preferences, and costs. Among these considerations, a prior history of myocardial infarction or stroke might favor choosing liraglutide as the second drug to be added to metformin. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Effects of testosterone therapy in older men with hypogonadism (April 2016)

Testosterone therapy has a number of benefits for hypogonadal young and middle-aged men, but its role in treating the decline in serum testosterone concentration that occurs with aging, in the absence of identifiable pituitary or hypothalamic disease, has been unclear. This was examined in the Testosterone Trials, three 12-month trials of testosterone gel versus placebo in 790 men over age 65 years with low serum testosterone and symptoms of hypogonadism (decreased libido, erectile dysfunction, low vitality) [25]. Initial results suggest that testosterone had a beneficial effect on sexual function, depressive symptoms and mood, and possibly physical function (walking distance). The rate of adverse events was similar with testosterone and placebo, but the risk of cardiovascular complications could not be assessed because of the size and duration of the trial. In the absence of known pituitary or testicular disease, we suggest testosterone therapy only for men with low serum testosterone concentrations on more than one occasion and symptoms of testosterone deficiency. Clinicians must discuss the uncertainty about the risks and benefits of testosterone therapy before recommending this approach. (See "Overview of testosterone deficiency in older men", section on 'The Testosterone Trials'.)

Cardiovascular effects of early versus late menopausal hormone therapy (April 2016)

The Women's Health Initiative reported that menopausal hormone therapy is associated with an excess risk of coronary heart disease, but accumulating data suggest that estrogen therapy started soon after menopause does not increase risk. In The Early versus Late Intervention Trial with Estradiol (ELITE), 643 postmenopausal women, stratified according to time since menopause (<6 or >10 years; early versus late, respectively), received oral estradiol (with progesterone for women with a uterus) or placebo for a median of five years [26]. Progression of subclinical atherosclerosis (measured as carotid intima-medial thickness) was slower with hormone therapy than with placebo in the early intervention group, while rates of progression were similar to placebo in the late intervention group. Estradiol had no effect on computed tomography measures of coronary artery calcium in either the early or late intervention group. (See "Menopausal hormone therapy: Benefits and risks", section on 'Younger postmenopausal women'.)

Metformin use and reduced kidney function (April 2016)

The use of metformin is contraindicated in patients with factors predisposing to lactic acidosis, including impaired renal function. The precise renal thresholds for the safe use of metformin remain uncertain. Improved clinical outcomes with metformin have been reported in observational studies of patients with diabetes and renal impairment (estimated glomerular filtration rate [eGFR] 45 to 60 mL/min). On the basis of these studies, the US Food and Drug Administration (FDA) revised its labeling of metformin, which previously had identified metformin as contraindicated in women and men with serum creatinine levels ≥1.4 mg/dL (124 micromol/L) and ≥1.5 mg/dL (133 micromol/L), respectively [27]. The use of metformin is contraindicated in patients with an eGFR <30 mL/min, and the initiation of metformin is not recommended in patients with an eGFR between 30 and 45 mL/min. For patients taking metformin whose eGFR falls below 45 mL/min, the benefits and risks of continuing treatment should be assessed, whereas metformin should be discontinued if the eGFR falls below 30 mL/min. For patients with eGFR between 30 and 60 mL/min, we typically reduce the metformin dose by half (no more than 1000 mg per day), although there are no data to support this approach. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)

Endocrine Society Statement: Bioidentical hormone therapy (April 2016)

The Endocrine Society has issued a Scientific Statement warning against the use of custom compounded "bioidentical hormone therapy" for managing menopausal symptoms [28]. This term refers to the use of custom-compounded, multi-hormone regimens (pills, gels, sublingual tablets, or suppositories) with dose adjustments based upon serial hormone monitoring. Compounded preparations typically include estradiol, estrone, estriol, progesterone, testosterone, and dehydroepiandrosterone (DHEA). Included among the key points were the absence of randomized trials demonstrating either efficacy or safety of compounded bioidentical hormone therapy for treating menopausal symptoms and the absence of regulatory oversight. When tested, potencies and patterns of absorption of compounded estrogens have been highly variable. Women who choose to take menopausal hormone therapy should be encouraged to use approved and regulated preparations of bioidentical hormones (for example, 17-beta estradiol and micronized progesterone). (See "Treatment of menopausal symptoms with hormone therapy", section on 'Bioidentical hormone therapy'.)

Diabetes as a coronary risk equivalent (March 2016)

Diabetes mellitus (DM) is frequently referred to as a "coronary risk equivalent," meaning that the risk of a coronary heart disease (CHD) event is similar between individuals with DM and individuals with known CHD. However, this “equivalency” averages together patients with widely varying CHD risks, and many patients with DM have much lower risks. This was examined in a prospective cohort study that followed more than 1.5 million adults (ages 30 to 90) for a median of 9.9 years [29]. The rate of new CHD events was lower in patients with DM than in those with a prior CHD event (12.2 versus 22.5 events per 1000 person-years); the risk of events was similar only in patients who had DM for more than 10 years. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Diabetes mellitus and CV risk'.)

ADULT GASTROENTEROLOGY

Toronto consensus for treatment of Helicobacter pylori (June 2016)

The Toronto consensus has published new guidelines for the treatment of Helicobacter pylori in adults [30]. These guidelines recommend a longer duration of treatment for all eradication regimens (14 versus 10 days), limiting the use of triple therapy to areas with low clarithromycin resistance or high eradication rates, and using quadruple (bismuth-containing or non-bismuth) therapy as a first line in all other areas. This is consistent with our approach. (See "Treatment regimens for Helicobacter pylori", section on 'Sequential therapy'.)

Rome IV criteria for functional gastrointestinal disorders (June 2016)

The Rome Foundation has released revised criteria (Rome IV) for the diagnosis of functional gastrointestinal disorders [31]. Examples of notable revisions include the changes to the criteria for irritable bowel syndrome and its subtypes, new criteria for reflux hypersensitivity, and inclusion of diagnoses with known etiologies that alter gut-brain interaction (eg, opioid-induced constipation). (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnostic criteria'.)

ADULT HEMATOLOGY AND ONCOLOGY

Duration of adjuvant endocrine therapy for breast cancer (July 2016)

For postmenopausal women receiving adjuvant treatment with an aromatase inhibitor (AI) for hormone-positive breast cancer, the standard duration of treatment has been five years. However, data from the MA17R trial demonstrated that a longer course of treatment improves disease-free survival (DFS) [32]. Among approximately 1900 postmenopausal women who had completed four and a half to six years of therapy with an AI, treatment for an additional five years improved five-year DFS relative to those who received placebo (95 versus 91 percent). There was no difference between the groups in regards to overall survival. Bone-related toxic effects were more frequent among those receiving extended treatment. Based on these results, we now offer an additional five years of treatment to those who have completed five years of AI therapy. However, it is reasonable for women with low risk of recurrence who are concerned about the risks and toxicities of extended treatment to omit extended treatment after a risk-benefit discussion. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)

Dosing of direct oral anticoagulants in obese patients (June 2016)

Limited data are available to guide dosing of direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) in patients with obesity. The International Society of Thrombosis and Hemostasis (ISTH) has issued guidance on this subject [33]. The major recommendations include use of DOACs at standard doses for those with a body mass index (BMI) ≤40 kg/m2 or weight <120 kg, and avoidance of DOACs in individuals with a BMI >40 kg/m2 or weight ≥120 kg. (See "Direct oral anticoagulants: Dosing and adverse effects".)

Zika virus and blood donation (March 2016, Modified April 2016)

The blood donor medical and travel history is used to identify and disqualify individuals who may be infected with Zika. Several agencies including the US Food and Drug Administration (FDA), World Health Organization (WHO), and AABB (an international organization) have issued guidance to reduce the risk of transmission in affected and unaffected areas [34-37]. These vary slightly but all include recommendations for deferral of individuals at risk of infection based on travel, symptoms, or sexual contacts, and recall and destruction of products if the donor develops symptoms of infection or diagnosis of Zika following donation. The WHO also recommends consideration of temporarily stopping collections and/or quarantining units until lack of symptoms can be confirmed. Currently used donor questionnaires are likely to identify individuals with symptomatic infection at the time of donation. The FDA has approved two investigational nucleic acid tests for Zika screening. (See "Blood donor screening: Medical history", section on 'Zika virus'.)

ADULT INFECTIOUS DISEASE

Condom use in HIV serodiscordant couples (August 2016)

HIV serodiscordant couples may question whether continued condom use is necessary for HIV prevention if the HIV-infected partner is on antiretroviral therapy (ART). One observational study followed over 900 serodiscordant couples (both heterosexual couples and men who have sex with men [MSM]) in whom the HIV-infected partner was virally suppressed on ART and who chose not to use condoms [38]. After more than 1200 couple-years of follow-up, there were no intra-couple transmission events. Ten MSM and one heterosexual partner acquired HIV infection during the study period, but viral sequence analysis suggested that these infections were not transmitted from the long-term HIV-infected partner. We continue to encourage condom use in HIV serodiscordant couples, as condoms offer protection from other sexually transmitted infections and provide back-up for potential periods of loss of virologic suppression. We advise couples who choose not to use condoms that the risk of HIV transmission in the setting of stable virologic suppression of the infected partner, while apparently negligible, cannot be ruled out completely. (See "HIV infection: Risk factors and prevention strategies", section on 'Serodiscordant couples'.)

HIV treatment to prevent transmission (August 2016)

Growing evidence has bolstered the concept that successful antiretroviral therapy (ART) of HIV-infected individuals substantially reduces the risk of sexual HIV transmission. Final analysis of a multinational randomized trial (HPTN 052) of over 1700 HIV serodiscordant heterosexual couples demonstrated that early ART for the HIV-infected partner, compared with delaying ART until certain clinical parameters were met, reduced HIV transmission risk by 93 percent [39]. All participants received condoms and risk reduction counseling. There were no linked transmissions (determined by detecting the same virus in both partners through viral sequencing) from HIV-infected individuals who had achieved stable viral suppression on ART; all eight linked transmissions from HIV-infected individuals using ART occurred within three months of ART initiation or in the setting of ART failure. This preventive benefit of ART is one of the reasons that early ART is recommended for all HIV-infected individuals, regardless of CD4 cell count. (See "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention' and "When to initiate antiretroviral therapy in HIV-infected patients", section on 'Benefits of antiretroviral therapy'.)

Mosquito-borne transmission of Zika virus in the continental United States (August 2016)

Zika virus is a mosquito-borne infection associated with congenital microcephaly and other birth defects among babies born to women infected during pregnancy. Mosquito-borne transmission of Zika virus was detected in Florida in July 2016, and in August 2016 the United States Centers for Disease Control and Prevention (CDC) issued an advisory recommending that pregnant women avoid travel to affected areas [40]. Updates regarding areas with Zika may be found on the CDC website (http://www.cdc.gov/zika/). (See "Zika virus infection: An overview", section on 'Travel advisories for pregnant women'.)

Sofosbuvir-velpatasvir for all genotypes of chronic HCV infection (July 2016)

All-oral, direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have proliferated over the past two years. Sofosbuvir-velpatasvir, a coformulated combination of an NS5B and an NS5A inhibitor, is the first such regimen that has high, well-established efficacy for all genotypes, even in patients with cirrhosis or prior treatment failure with interferon-based regimens [41-43]. This agent was approved by the US Food and Drug Administration in June 2016 and is now our preferred or one of our preferred regimens for adults with chronic HCV infection of any genotype because of its efficacy, simplicity of administration, and limited drug interactions. Sofosbuvir-velpatasvir is given for 12 weeks for all genotypes. For genotype 3 infection, the addition of ribavirin may be warranted, depending on the presence of cirrhosis, the prior treatment history, and the presence of mutations associated with NS5A resistance. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Selection of treatment regimens'.)

Treatment failure of pharyngeal gonorrhea following combination antimicrobial therapy (July 2016)

Because of concerns about the decreasing susceptibility of Neisseria gonorrhoeae to several classes of antibiotics, combination antimicrobial therapy with ceftriaxone plus a second agent, preferably azithromycin, is the recommended treatment for uncomplicated gonorrhea. However, treatment failure following combination therapy has now been reported, in a heterosexual man from the United Kingdom who presented with both urogenital and pharyngeal infection [44]. Although the urogenital infection was successfully treated with ceftriaxone plus azithromycin, the pharyngeal infection persisted, and decreased susceptibility to both agents was detected in the post-treatment isolate. This report, in addition to surveillance reports suggesting increasing rates of decreased susceptibility to azithromycin in N. gonorrhoeae isolates in the United States [45], highlights the need for novel treatment strategies for gonorrhea in the face of rising antimicrobial resistance. (See "Treatment of uncomplicated gonococcal infections", section on 'Monitoring for and managing treatment failure' and "Treatment of uncomplicated gonococcal infections", section on 'Rationale for dual therapy'.)

USPSTF recommendations on syphilis screening in nonpregnant adults and adolescents (June 2016)

In June 2016, the United States Preventive Services Task Force updated its statement on syphilis screening in asymptomatic nonpregnant adolescents and adults to recommend screening for those who are at high risk for infection [46]. These include sexually active men who have sex with men (MSM), HIV-infected patients, and individuals with a history of incarceration or commercial sex work. The optimal frequency of routine screening in high-risk patients without a clear exposure is yet to be determined. Consistent with other expert guidelines, we suggest annual screening for sexually active MSM and HIV-infected individuals, with more frequent screening for those with high-risk behaviors, such as multiple or anonymous sexual partners. (See "Syphilis: Screening and diagnostic testing", section on 'Asymptomatic patients' and "Screening for sexually transmitted infections".)

Shortage of benzathine penicillin G (Bicillin L-A) (May 2016)

In May 2016, the United States Centers for Disease Control and Prevention reported a manufacturing delay of benzathine penicillin G (Bicillin L-A), which is the treatment of choice for all stages of syphilis [47]. In light of potential shortages of this agent, it is important for clinicians to note that only a single dose of benzathine penicillin G is warranted for early syphilis. Pregnant women with syphilis should be prioritized for benzathine penicillin G, and so alternative regimens, such as doxycycline, may need to be used for nonpregnant adults if supplies are limited. Bicillin C-R (equal concentrations of procaine and benzathine penicillin G) should not be used to treat syphilis. (See "Syphilis: Treatment and monitoring", section on 'Penicillin as the treatment of choice'.)

Restriction of fluoroquinolone use in uncomplicated infections (May 2016)

The US Food and Drug Administration (FDA) has stated that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits for patients with uncomplicated acute sinusitis, acute bronchitis, and urinary tract infections who have other treatment options [48]. For patients with these infections, fluoroquinolones should be reserved for those who have no alternative treatment options. This announcement was based on an FDA safety review showing that systemic fluoroquinolone use is associated with disabling and potentially permanent serious side effects, including those involving the tendons, muscles, joints, nerves, and central nervous system. (See "Fluoroquinolones", section on 'Restriction of use for uncomplicated infections'.)

Viral dynamics and symptom onset in acute HIV infection (May 2016)

A recent study that closely followed 50 acutely HIV-infected patients who had been identified by prospective viral testing of high-risk individuals provides precise information on the clinical features and viral dynamics shortly following infection [49]. Although almost all subjects had at least one reported symptom or sign during the first four weeks of infection, these were mainly short-lived, nonspecific, and unlikely to have brought the individual to clinical attention outside of a study setting. The highest frequency of symptoms and signs were observed just before peak viremia occurred, approximately two weeks after the initial detection of viral RNA. These results highlight the difficulty of suspecting acute HIV infection by clinical features alone and thus, the importance of repeated HIV screening in high-risk individuals. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Nonoccupational postexposure prophylaxis to prevent HIV infection (April 2016)

A discrete course of antiretroviral therapy (ART) administered after a possible exposure to HIV may reduce the risk of HIV acquisition. The US Centers for Disease Control and Prevention (CDC) has issued updated guidelines on HIV prophylaxis following a nonoccupational exposure [50]. A 28-day course of a three-drug regimen (eg, tenofovir disoproxil fumarate-emtricitabine plus either raltegravir or dolutegravir) should be offered to patients who present within 72 hours of a high-risk exposure (eg, condomless receptive or insertive vaginal or anal intercourse or a percutaneous exposure to blood or bloody body fluids) from a source who is HIV-infected or is at high risk for HIV infection. Exposed patients should be educated about the signs and symptoms of acute HIV infection, and have follow up HIV testing. (See "Nonoccupational exposure to HIV in adults".)

Indications for antibiotics in the management of skin abscess (March 2016)

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has raised uncertainty regarding the role of antimicrobial therapy for treatment of skin abscess following incision and drainage. In a randomized trial including 1220 patients >12 years of age (median 35 years) with drained skin abscess (≥2 cm in diameter) comparing trimethoprim sulfamethoxazole (TMP-SMX, 320 mg/1600 mg twice daily) with placebo, the cure rate 7 to 14 days after treatment was higher in the TMP-SMX group (80.5 versus 73.6 percent); wound cultures were positive for MRSA in 45 percent of cases [51]. Based on these findings, abscess size ≥2 cm in diameter is a useful threshold for guiding decisions regarding use of antibiotic therapy for adjunctive treatment of skin abscess.

Additional factors for which we recommend antibiotic therapy include the presence of multiple lesions, extensive surrounding cellulitis, associated comorbidities or immunosuppression, signs of systemic infection, or inadequate clinical response to incision and drainage alone; we suggest antibiotic therapy for patients with an indwelling device or high risk for transmission of S. aureus to others. For otherwise healthy patients with none of these factors, we suggest not administering antimicrobial therapy. (See "Skin abscesses, furuncles, and carbuncles", section on 'Role of antibiotics'.)

Zika virus and Guillain-Barre syndrome (March 2016)

Zika virus has been associated with Guillain-Barre syndrome (GBS), although a direct causal relationship has not been definitively established. A case-control study in French Polynesia evaluated the association between GBS and Zika virus infection during the 2013 to 2014 outbreak [52]. Cases included 42 patients diagnosed with GBS; one control group included 98 patients with nonfebrile illnesses and a second control group included 70 patients with Zika virus infection in the absence of neurological complications. Zika IgM was positive in 93 percent of GBS cases (versus 17 percent of patients in the first control group); serologic evidence of past dengue infection was similar among all three groups. Antiglycolipid IgG antibodies were detected in fewer than 50 percent of GBS cases, raising the possibility of direct viral neurotoxicity. Results of nerve conduction studies were consistent with the acute motor axonal neuropathy type of GBS; clinical improvement during follow-up suggested reversible conduction failure. Symptoms of Zika virus infection occurred in 88 percent of patients with GBS; the median interval between viral syndrome and onset of neurological symptoms was six days. All GBS cases received intravenous immune globulin, 38 percent required intensive care, and 29 percent needed respiratory care; all survived. The incidence of GBS during the outbreak was estimated to be 0.24 cases per 1000 Zika virus infections. (See "Zika virus infection: An overview", section on 'Guillain-Barré syndrome'.)

Oral fluoroquinolone use and serious arrhythmia (March 2016)

QT interval prolongation and torsades de pointes have been associated with fluoroquinolone use, but the degree to which fluoroquinolones block cardiac potassium channels and thereby cause QT prolongation varies by agent. The risk of serious arrhythmia during fluoroquinolone therapy was evaluated in a cohort of adults aged 40 to 79 years of age in Denmark and Sweden; arrhythmic events were compared for 909,656 courses of fluoroquinolones (ciprofloxacin in 83 percent, norfloxacin in 12 percent, ofloxacin in 3 percent, moxifloxacin in 1 percent, other in 1 percent) and 909,656 courses of penicillin, an antibiotic not associated with arrhythmia [53]. There was no increase in the risk of serious arrhythmia with fluoroquinolones compared with penicillin. This finding conflicts with results from earlier studies, and may be explained in part by the predominant use of ciprofloxacin in this cohort, with its smaller impact on QT prolongation. (See "Fluoroquinolones", section on 'QT interval prolongation and arrhythmia'.)

Behavioral interventions to decrease inappropriate antibiotic prescribing (February 2016)

Behavioral interventions may decrease inappropriate antibiotic prescribing for upper respiratory tract infections (URIs). A randomized trial among primary care practices compared provider education with antibiotic prescribing guidelines (control group) with behavioral interventions to decrease antibiotic prescribing for patients with nonspecific URIs, acute bronchitis, or influenza [54]. The interventions were: (1) suggesting nonantibiotic alternative treatments (eg, decongestants, cough suppressants, ipratropium) via electronic order sets; (2) prompting clinicians to justify prescribing; and (3) peer comparison. Rates of inappropriate prescribing decreased in all groups, including the control group, but the decrease in the groups using prompting to justify prescribing and peer comparison was greater than in the control group. (See "Acute bronchitis in adults", section on 'Lack of efficacy of routine antibiotic therapy'.)

ADULT NEPHROLOGY AND HYPERTENSION

Goal blood pressure in older adults (June 2016)

Goal blood pressure in older adults was examined in the Systolic Pressure Intervention Trial (SPRINT) [55]. SPRINT enrolled a subgroup of more than 2600 ambulatory adults aged 75 years or older, including 349 categorized as being fit, 1456 as less fit, and 815 as frail according to a validated frailty index. At 3.1 years, rates of both the primary cardiovascular endpoint and all-cause mortality were significantly lower among those assigned more intensive (goal <120 mmHg) versus less intensive (goal <140 mmHg) systolic blood pressure lowering. The benefit from more intensive blood pressure control was present in both fit and frail older adults. Serious adverse events were similar in the two treatment groups, and did not depend upon frailty. (See "Treatment of hypertension in the elderly patient, particularly isolated systolic hypertension", section on 'Goal blood pressure'.)

Antihypertensive therapy in patients not at high cardiovascular risk (April 2016)

The benefit of antihypertensive therapy in patients at low or moderate cardiovascular risk, including those who are normotensive, is unclear. The Third Heart Outcomes Prevention Evaluation trial (HOPE-3) randomly assigned 12,705 patients at moderate risk for cardiovascular disease (only 38 percent were hypertensive at baseline) to receive a fixed-dose combination of candesartan plus hydrochlorothiazide or placebo [56]. At 5.6 years, there was no significant difference in cardiovascular events. However, among a hypertensive subgroup (ie, those whose initial systolic pressure was in the highest tertile, or greater than 143 mmHg), antihypertensive therapy significantly reduced the incidence of major cardiovascular events (5.7 versus 7.5 percent, absolute benefit of 1.8 percent). Thus, antihypertensive therapy reduced cardiovascular events in patients with mild hypertension and low overall cardiovascular risk. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Benefit in those with mild hypertension'.)

ADULT NEUROLOGY AND PSYCHIATRY

Early benefit of aspirin after TIA and ischemic stroke (July 2016)

The risk of recurrent ischemic stroke is highest in the first days and weeks after transient ischemic attack (TIA) and ischemic stroke, but the benefit of aspirin in this time period has not been well studied. In a recent pooled analysis of data from over 15,000 subjects in 12 trials evaluating aspirin for secondary prevention, the benefit of aspirin was strongest in the early weeks after TIA or ischemic stroke [57]. Compared with control (mostly placebo), aspirin reduced the relative risk of recurrent ischemic stroke within the first six weeks by 58 percent (1 versus 2.4 percent, absolute risk reduction 1.4 percent). The benefit of aspirin in this time frame was greatest for the subgroup of patients with TIA or minor stroke. These findings emphasize that aspirin should be started as early as possible after the diagnosis of TIA or ischemic stroke is confirmed. (See "Antiplatelet therapy for secondary prevention of stroke", section on 'Aspirin'.)

Treatment of binge eating disorder (July 2016)

Several psychotherapies and medications have been studied for treating binge eating disorder. In a recent systematic review and meta-analysis of trials evaluating the efficacy of different treatment options compared with no treatment or placebo, there was strong evidence supporting the use of therapist-led cognitive-behavior therapy (CBT), lisdexamfetamine, or second-generation antidepressants (eg, selective serotonin reuptake inhibitors) [58]. In addition, less compelling evidence indicated that patients can achieve abstinence with self-help CBT or topiramate. We regard CBT as first-line treatment; however, no head-to-head trials have compared the efficacy of different active treatments. (See "Binge eating disorder in adults: Overview of treatment", section on 'Cognitive-behavior therapy'.)

Safety of smoking cessation medications in patients with and without mental health disorders (May 2016)

Reports of newly emergent depression, suicidal ideation, and suicidal behavior among patients receiving bupropion or varenicline for smoking cessation raised questions about the safety of these drugs in smokers with mental health disorders. In a recent trial examining the safety of these medications, more than 8000 motivated adult smokers, approximately half with clinically stable mental disorders, were randomly assigned to varenicline, bupropion, transdermal nicotine, or placebo for 12 weeks [59]. Compared with patients without mental health disorders, patients with such disorders were more likely to experience neuropsychiatric adverse events (including anxiety, depression, agitation, or hostility) during treatment (2.1 versus 5.8 percent). However, in both patients with and without mental health disorders, the rate of events did not differ for patients assigned to varenicline or bupropion compared with placebo. Rates of smoking abstinence were higher for each of the three drugs compared with placebo, and higher with varenicline compared with bupropion or transdermal nicotine. The findings are consistent with previous, smaller trials supporting carefully monitored use of smoking-cessation medications in smokers with stable mental health disorders. (See "Pharmacotherapy for co-occurring schizophrenia and substance use disorder", section on 'Safety' and "Pharmacotherapy for smoking cessation in adults", section on 'Neuropsychiatric effects'.)

Stenting versus surgery for carotid artery stenosis (March 2016)

Two recent studies have compared carotid artery stenting (CAS) and carotid endarterectomy (CEA) for treatment of carotid artery stenosis. Accumulating evidence suggests that both CAS and CEA provide similar long-term outcomes for patients with asymptomatic and symptomatic carotid occlusive disease, although the periprocedural risk of stroke and death is higher with CAS.

In a meta-analysis of older adult patients with symptomatic carotid disease, pooled patient-level data from four trials found that the periprocedural risk of stroke and death increased with age (hazard ratio [HR] 2.2 for ages 65 to 69 and 4.2 for age ≥80 years) for patients assigned to CAS, while there was no increase in periprocedural risk by age for CEA [60]. The periprocedural risk of stroke and death was significantly increased with CAS compared with CEA for patients age 70 and older. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Effect of age'.)

The ACT I randomized trial in patients with asymptomatic 70 to 99 percent carotid stenosis assigned 1453 patients to either CAS or CEA [61]. For the primary composite endpoint (death, stroke, or myocardial infarction within 30 days of the procedure or ipsilateral stroke within one year), the prespecified statistical margin for noninferiority of stenting compared with endarterectomy was met. The cumulative five-year rates of stroke-free survival at CAS and CEA were 93.1 and 94.7 percent, respectively. (See "Management of asymptomatic carotid atherosclerotic disease", section on 'Stenting trials'.)

Because of higher rates of short-term complications with CAS, we continue to prefer CEA for most medically stable patients who have symptomatic carotid stenosis or who have a life expectancy of at least five years and high grade (≥80 percent) asymptomatic carotid stenosis at baseline or progression to ≥80 percent stenosis despite intensive medical therapy.

Growing concern over herb used in self-treatment of opioid withdrawal (March 2016)

Kratom (Mitragyna speciosa), an herb with opioid and stimulant-like properties used in self-treatment of opioid withdrawal, has been subject to international attention due to an increase in overdose-associated hospital visits and deaths [62]. Published investigation of kratom's efficacy and toxicity has been limited to case reports/series. Frequent and prolonged ingestion for pain or recreational use has been associated with anorexia, weight loss, seizures, and psychosis. In the United States, kratom is not regulated by the Food and Drug Administration, though individual states and some countries prohibit its use. (See "Medically supervised opioid withdrawal during treatment for addiction", section on 'Alternative treatments'.)

Declining incidence of dementia (February 2016)

A growing number of studies indicate that the incidence of dementia may be declining in high-income countries, concomitant with a decline in the prevalence of many vascular risk factors. As an example, using data from over 5000 patients enrolled in the Framingham Heart Study in the United States, the five-year cumulative hazard rate for dementia fell from 3.6 per 100 persons during the late 1970s to 2.0 per 100 persons in the late 2000s [63]. The risk reduction was only found among individuals with at least a high school diploma, and the magnitude of the change was higher for vascular dementia than for Alzheimer disease. Rates of hypertension, stroke, and atrial fibrillation also fell over the same time period, while rates of obesity and type 2 diabetes rose, and it is not certain what factors account for the decreased incidence of dementia. Despite these trends, the global total burden of dementia is expected to continue rising as the population ages. (See "Treatment and prevention of vascular dementia", section on 'Risk factor management'.)

ADULT PULMONOLOGY

Combination inhaled glucocorticoid/long-acting beta agonists in patients with COPD and cardiovascular risk factors or disease (May 2016)

While the evidence has been generally reassuring about the safety of combination inhaled glucocorticoid plus long-acting beta agonist (ICS-LABA) inhalers in patients with chronic obstructive pulmonary disease (COPD), patients with known cardiovascular disease (CVD) were excluded from previous clinical trials. In the three-year randomized trial, Study to Understand Mortality and MorbidITy (SUMMIT), the effect of the fluticasone furoate-vilanterol combination inhaler was compared with the individual components and placebo in almost 17,000 patients with moderate COPD (FEV1 between 50 and 70 percent of predicted) and known or increased risk of CVD [64]. Relative to placebo, the combination inhaler did not affect all-cause mortality or composite cardiovascular events. Thus, the presence of CVD should not affect the role of ICS-LABA inhalers in COPD. (See "Management of the patient with severe COPD and cardiovascular disease", section on 'Combination inhaled bronchodilator plus glucocorticoid'.)

Safety of fluticasone-salmeterol combination therapy in asthma (March 2016)

In early studies, a small increase in asthma-related deaths associated with salmeterol led the US Food and Drug Administration to place a boxed warning on the use of salmeterol in asthma. While concerning, the number of events was small, and the magnitude of the risk was unclear. In addition, it could not be determined if the potential risk of salmeterol could be mitigated by combining it with an inhaled glucocorticoid. The safety of salmeterol in combination with fluticasone has been assessed in a multicenter trial, in which almost 12,000 adolescents and adults with persistent asthma were randomly assigned to take inhaled fluticasone or the combination of inhaled fluticasone-salmeterol (in a single inhaler) for 26 weeks [65]. The rate of serious asthma-related adverse events was similar in the two groups, and no deaths occurred in either group. In addition, no difference was noted in the rate of asthma-related hospitalizations. Thus, for patients over age 12 who do not have a history of life-threatening asthma events, data are reassuring about the safety of fluticasone-salmeterol in a fixed-dose inhaler. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)

ADULT RHEUMATOLOGY

Tai Chi for patients with knee osteoarthritis (June 2016)

Tai Chi, a multicomponent traditional Chinese mind-body practice, combines slow and graceful movements with meditative relaxation techniques and can reduce pain and improve physical function in patients with osteoarthritis (OA), compared with control interventions. In a recent randomized trial involving over 200 patients with knee OA, a Tai Chi program (twice weekly for 12 weeks, with instruction to practice Tai Chi daily), resulted in benefit similar to an active comparator, outpatient physical therapy and a home exercise program [66]. After 12 weeks, both groups exhibited statistically and clinically significant reduction in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score, and differences between the groups were not statistically significant. Benefits were maintained at 52 weeks of follow-up. The Tai Chi group had greater improvements in depression and the physical quality-of-life measure. (See "Nonpharmacologic therapy of osteoarthritis", section on 'Tai Chi'.)

Acetaminophen for knee and hip osteoarthritis (May 2016)

Treatment with acetaminophen (paracetamol, N-acetyl-p-aminophenol [APAP]) appears to be slightly more effective than no treatment in relieving overall pain from osteoarthritis (OA), but generally less effective than nonsteroidal antiinflammatory drugs (NSAIDs). This was recently illustrated in a 2016 network meta-analysis of randomized trials involving nearly 60,000 patients with knee or hip OA receiving either APAP, one of seven NSAIDs, or placebo [67]. The summary estimates of benefit with APAP were extremely low, although statistically significant, for the highest dose of APAP, but less than the predefined minimum clinically important effect. These results do not exclude the possibility that some patients respond, while many others do not. In patients with OA lacking signs or symptoms of inflammation, we initiate pharmacologic therapy with acetaminophen on an as-needed basis. If this is inadequate, we advise a trial of acetaminophen on a scheduled basis up to three to four times daily. Such use is consistent with evidence supporting its modest benefit compared with placebo and its relative safety. (See "Initial pharmacologic therapy of osteoarthritis", section on 'Noninflammatory OA'.)

Vitamin D ineffective for osteoarthritis (March 2016)

Low vitamin D levels have been associated with osteoarthritis (OA) in observational studies, but randomized trials of vitamin D for the treatment of OA have had mixed results. In the largest of the randomized trials, involving over 400 patients with symptomatic knee OA and low levels of 25-hydroxyvitamin D, compared with placebo, monthly treatment for two years with cholecalciferol did not improve knee pain and did not reduce tibial cartilage volume loss or bone marrow lesions as assessed by MRI [68]. We do not recommend dietary supplementation with vitamin D for the treatment of OA. (See "Nonpharmacologic therapy of osteoarthritis", section on 'Diet and vitamins'.)

Oral glucocorticoids for acute gout flare (March 2016)

The use of oral glucocorticoids as first-line therapy in patients with an acute gout flare, rather than nonsteroidal antiinflammatory drugs or colchicine, is a matter of debate. In a randomized trial, over 400 patients with acute gout presenting to an emergency department within three days of symptom onset were treated with either prednisolone or indomethacin for five days [69]. There was no significant difference between the groups in the degree of pain reduction, and no serious adverse events occurred with either therapy. Although effective in this trial, glucocorticoid use in acute gout is associated with an increased risk of rebound attacks, especially in patients with frequent flares and those not receiving prophylactic therapy, in whom tapering over 10 days or longer may be advisable. (See "Treatment of acute gout", section on 'Oral glucocorticoids'.)

GYNECOLOGY

Atypical glandular cells on cervical cytology associated with immediate and long-term risks of cervical cancer (March 2016)

Women with atypical glandular cells (AGC) on cervical cytology appear to be at increased risk for cervical cancer in both the short and long term. A recent study used data from Swedish national registries to analyze outcomes of over 14,000 women with AGC on their first recorded cervical cancer screening test [70]. Immediately following an AGC result, adenocarcinoma was identified in 0.99 percent of women and squamous carcinoma in 0.30 percent. Compared with women with normal cytology at their first recorded cervical cancer screening test, women with AGC continued to be at higher risk of cervical cancer for up to 15.5 years. The highest risk of cervical cancer was in the first 3.5 years, and then decreased over time. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells", section on 'Histology and site of lesion'.)

OBSTETRICS

Safety of intranasal triamcinolone for allergic rhinitis in pregnancy (July 2016)

Intranasal glucocorticoid sprays are highly effective for treatment of allergic rhinitis, but concerns remain about their use in pregnancy. The overall safety of intranasal glucocorticoids in pregnancy was supported by an observational cohort study of over 140,000 pregnant women, of whom 2502 were exposed to these medications during the first trimester [71]. Exposure was not associated with increased rates of miscarriage or overall rates of major congenital malformations compared with non-exposure. Triamcinolone was the only intranasal glucocorticoid of potential concern; first trimester use was associated with abnormalities of the respiratory system and choanal atresia. Although these findings are not conclusive, we prefer to use other intranasal glucocorticoids in the first trimester, such as intranasal mometasone, fluticasone, or budesonide, pending further data [72]. (See "Recognition and management of allergic disease during pregnancy", section on 'Glucocorticoid nasal sprays'.)

Antenatal steroids at 34 to 37 weeks for pregnancies at high risk of preterm birth (February 2016)

Antenatal corticosteroid therapy at 23 to 34 weeks of gestation for women at risk for preterm delivery reduces the incidence and severity of respiratory distress syndrome in offspring delivered within seven days of administration. Steroids have not been administered after 34 weeks because studies have not demonstrated a benefit, although data have been sparse. Recently, the Antenatal Late Preterm Steroids (ALPS) Trial randomly assigned women at 340/7ths to 365/7ths weeks of gestation at high risk for late preterm birth to receive a first course of antenatal betamethasone or placebo and found that the frequency of a composite outcome of neonatal respiratory problems was reduced in the betamethasone group [73]. Based on these data, we believe offering a first course of antenatal corticosteroids to patients scheduled for cesarean delivery at 340/7ths to 366/7ths weeks is reasonable. We would not administer a first course of steroids to women at 340/7ths to 366/7ths weeks planning vaginal delivery as transient tachypnea of the newborn is less common after labor and vaginal birth. For women in whom delivery at 340/7ths to 366/7ths is uncertain (eg, threatened preterm labor), we would not administer a course of steroids because of the potential for long-term harm with no benefit if the patient does not deliver preterm. For women at 340/7ths to 366/7ths weeks who received a course of antenatal corticosteroids earlier in pregnancy, we would not administer a second course as the benefits and risks have not been studied in this population. This approach limits late preterm in utero steroid exposure to pregnancies certain to deliver preterm and with neonates at most risk for experiencing serious respiratory problems from transient tachypnea of the newborn. We do not administer steroids to women undergoing scheduled cesarean delivery at ≥37 weeks: the overall risk of respiratory illness at this gestational age is low and rarely serious. (See "Antenatal corticosteroid therapy for reduction of neonatal morbidity and mortality from preterm delivery", section on 'After 34 weeks'.)

PEDIATRICS: GENERAL PEDIATRICS

Lipid screening in children and adolescents (August 2016)

Increasing evidence suggests that atherosclerosis begins in childhood and adolescence, yet the optimal strategies for early screening and treatment of the disease remain uncertain. A recent statement of the US Preventive Services Task Force (USPSTF) concluded that the available evidence on screening for lipid disorders in children and adolescents is insufficient to assess the balance of benefits and harms of screening [74]. This position is unchanged from the 2007 USPSTF statement; however, it contradicts the 2011 National Heart, Lung, and Blood Institute (NHLBI) guidelines for cardiovascular health and risk reduction, which recommend screening in all children and adolescents and have been endorsed by the American Academy of Pediatrics (AAP) and the American Heart Association (AHA) [75]. We continue to suggest both age-based universal and selective screening for pediatric dyslipidemia. (See "Dyslipidemia in children: Definition, screening, and diagnosis", section on 'Recommendations of others'.)

Absence of pyuria in children with UTI (July 2016)

The diagnosis of urinary tract infection (UTI) in children is usually based on the finding of significant bacteriuria plus pyuria. However, in a retrospective review of 1181 children <18 years of age with symptomatic UTI and significant growth of a single uropathogen, microscopic urinalysis did not show pyuria in 13 percent [76]. The frequency of pyuria was lower in children with Enterococcus (54 percent), Pseudomonas aeruginosa (62 percent), and Klebsiella (74 percent) than in children with E. coli (89 percent). Therefore, if the urine culture of a child with UTI symptoms demonstrates significant growth (≥50,000 colony-forming units [CFU]/mL from a catheterized specimen or ≥100,000 CFU/mL from a clean voided specimen) of Enterococcus, Klebsiella, or P. aeruginosa, UTI may be diagnosed in the absence of pyuria. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Pyuria'.)

Mild skin-limited allergic reactions to antibiotics in children (June 2016)

It is not uncommon for young children to develop mild skin-limited reactions (eg, rash, hives) to antibiotics, particularly amoxicillin, during treatment for routine infections. Most of these reactions do not represent serious drug allergy, but IgE-mediated anaphylaxis can first present in this manner, so caution is necessary. In a new study of over 800 young children referred to an allergy clinic with past mild cutaneous reactions to amoxicillin, all children underwent a two-step challenge [77]. Ninety-four percent had no reaction, 2 percent had mild immediate reactions (isolated hives), and 4 percent had mild delayed reactions. Skin testing was later performed on the subset with immediate initial reactions, and only 1 of 17 children had a positive result, indicating that skin testing would not have been useful in identifying these children before challenge. At present, we do not advocate this approach unless there is no alternative antibiotic and allergy referral is not available. However, this study provides valuable information about the pathophysiology of this common type of reaction and may allow for safe rechallenge protocols to be developed in the future for use in the primary care setting. (See "Penicillin allergy: Delayed hypersensitivity reactions", section on 'Children'.)

Nebulized hypertonic saline does not reduce length of stay in children with bronchiolitis (June 2016)

In previous meta-analyses, compared with a placebo (nebulized normal saline), nebulized hypertonic saline appeared to reduce the length of stay in children hospitalized with bronchiolitis, but the findings were limited by heterogeneity. A new meta-analysis reanalyzed the data controlling for the major sources of heterogeneity (imbalance in duration of illness between treatment groups and a widely divergent outcome definition in one study population) [78]. In the reanalysis, nebulized hypertonic saline had no effect on length of stay. This finding supports our suggestion against the routine use of nebulized hypertonic saline in hospitalized children with bronchiolitis. Maintenance of adequate hydration, provision of oxygen and respiratory support as necessary, monitoring disease progression, and anticipatory guidance are the mainstays of management of severe bronchiolitis. (See "Bronchiolitis in infants and children: Treatment; outcome; and prevention", section on 'Nebulized hypertonic saline'.)

Diluted apple juice for hydration in young children with mild gastroenteritis (May 2016)

Commercial oral rehydration solutions (ORS) are recommended for rehydration of children with gastroenteritis. More readily available household beverages, such as fruit juice, tea, sports drinks, and soft drinks, have not been recommended due to concerns that their lower sodium concentration and higher osmolarity could induce osmotic diarrhea, leading to hyponatremia. However, a randomized trial in children 6 to 60 months of age with mild gastroenteritis and no clinical signs of dehydration demonstrated that hydration with half-strength apple juice resulted in fewer episodes of treatment failure than ORS (17 versus 25 percent) [79]. Treatment failure was defined as any of the following events occurring within seven days of enrollment: intravenous rehydration, hospitalization, subsequent unscheduled physician encounter, protracted symptoms, crossover to the other fluid, ≥3 percent weight loss, or signs of significant dehydration on a follow-up visit. Based on these findings, diluted apple juice followed by a permissive approach to fluid consumption is a reasonable alternative to ORS for hydration in young children with mild gastroenteritis and no clinical signs of dehydration. (See "Oral rehydration therapy", section on 'Common household beverages and fluids'.)

BMI during adolescence and cardiovascular mortality during adulthood (April 2016)

A variety of studies have shown associations between obesity during adolescence and multiple cardiovascular risk factors (eg, hypertension, dyslipidemia, diabetes). Now, a large population-based study from Israel found that higher body mass index (BMI) during late adolescence is associated with cardiovascular mortality in mid-adulthood [80]. Of note, this association was seen even within the range of BMIs considered to be normal in adolescents, with a graded increase in risk of death as adolescent BMI rose above the 50th percentile. This study supports and expands the body of evidence suggesting that the processes causing coronary heart disease begin during adolescence. (See "Comorbidities and complications of obesity in children and adolescents", section on 'Adult coronary heart disease'.)

Increasing vegetable consumption in children (April 2016)

Vegetables are an important component of a healthy diet, but national surveys indicate that vegetable consumption by young children falls short of the recommended 2.5 cup-equivalents per day. In a longitudinal study, six-year old children who had been offered a variety of vegetables at the initiation of complementary feedings were more willing to try new vegetables, ate more new vegetables, and liked new vegetables more than children who were offered little or no variety of vegetables [81]. Offering a vegetable that was initially disliked at eight subsequent meals was associated with increased acceptance of that vegetable and continuing to like and eat that vegetable at three and six years of age. These findings support recommendations to offer vegetables at least once per day, to offer a variety of vegetables, and to offer vegetables that are initially refused at subsequent meals. (See "Introducing solid foods and vitamin and mineral supplementation during infancy", section on 'Puréed foods'.)

Early introduction of highly allergenic foods in infancy (March 2016)

The Enquiring about Tolerance (EAT) trial examined whether early introduction of six highly allergenic foods (peanut, hen’s egg, cow's milk, sesame, whitefish, and wheat) beginning at three months of age, compared with exclusive breastfeeding until approximately 6 months of age, protected against the development of food allergy in over 1300 breastfed infants recruited from the general population [82]. Early food introduction did not reduce breastfeeding, although caregivers found the feeding regimen to be challenging, with only 43 percent of the participants in the early-introduction group adhering to the protocol. No difference was seen in the prevalence of food allergy at one and three years of age between the two groups in the intention-to-treat (ITT) analysis. However, in the per-protocol analysis, the prevalence of any food allergy, and peanut and egg allergy in particular, was lower in the early-introduction group compared with the standard-introduction group (2.4 versus 7.3 percent, respectively, for any food allergy). Thus, although the more rigorous ITT analysis did not show a benefit of introduction at three months and further research is needed, the results are consistent with our current recommendation to not withhold allergenic foods, and to introduce them as early as 4 to 6 months of age. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in the general population'.)

Standardized evaluation and management plan for children with syncope (February 2016)

Although the etiology of syncopal events in children is most often benign, syncope can also occur as the result of more serious (usually cardiac) disease with the potential for sudden death. The goal of the evaluation of a child with syncope is to identify life-threatening conditions, as well as conditions that are associated with the risk of significant injury. In most children, cardiac syncope is suggested by a careful history, physical examination, and electrocardiogram (ECG). In a prospective, multicenter observational study of over 1200 children with syncope evaluated by a pediatric cardiologist using a standardized outpatient evaluation and management plan (based upon history, physical examination, and ECG), 85 percent of patients were diagnosed with typical (vasovagal) syncope [83]. One patient with cardiac syncope caused by hypertrophic cardiomyopathy was identified using the standardized evaluation plan. This patient had exercise-induced syncope and abnormal findings on ECG. This study suggests that cardiac causes for syncope are rare in children and can usually be identified by clinical findings and an ECG. (See "Emergent evaluation of syncope in children and adolescents", section on 'Evaluation and decision'.)

Nonoperative management for children with uncomplicated appendicitis (February 2016)

Urgent appendectomy is routine practice for children with appendicitis. However, preliminary evidence suggests that nonoperative management (observation and intravenous antibiotics for 24 hours) may be safely performed in selected patients at low risk for perforation. In a prospective, observational study of 102 older children (median age 12 years) with acute uncomplicated appendicitis who were offered surgery or nonsurgical management at a children’s hospital, 28 of the 37 patients who with their families chose nonoperative management had not required appendectomy at one year [84]. When compared with children who underwent immediate appendectomy, children who received nonoperative management had a longer length of stay at initial hospitalization (median difference 17 hours) but, at one year, fewer days not participating in normal activities (median 13 fewer days) and lower appendicitis-related healthcare costs (median savings USD $810). Although these preliminary findings indicate potential benefits for selected children with acute, uncomplicated appendicitis who undergo nonoperative management, more information regarding longer-term outcomes in a much larger cohort of patients is needed before to better determine which patients can benefit from this approach. (See "Acute appendicitis in children: Management", section on 'Nonoperative management'.)

PEDIATRICS: DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS

Discontinuation of desmopressin treatment of nocturnal enuresis in children (July 2016)

Desmopressin is an effective short-term treatment for nocturnal enuresis in children, but relapse rates are high after discontinuation. A recent meta-analysis of four randomized trials including 500 patients demonstrated the benefit of tapering desmopressin rather than abrupt discontinuation (sustained response rate: 57 versus 42 percent) [85]. In subgroup analyses, gradually decreasing the effective dose prevented relapse, but increasing the interval between doses did not. When discontinuing daily desmopressin, we suggest decreasing the daily dose rather than extending the interval between doses or abrupt discontinuation. (See "Nocturnal enuresis in children: Management", section on 'Discontinuation'.)

Screening for autism spectrum disorder (March 2016)

Autism spectrum disorder (ASD) is common, with a prevalence of 1 in 50 to 1 in 500 children. Symptoms of ASD often are present before 18 months of age, but the average age of diagnosis is >4 years. Early identification is hampered by the heterogeneous presentation and the difficulty of differentiating symptoms of ASD from those of other developmental disorders. In February 2016, the United States Preventive Services Task Force concluded that there is insufficient evidence to adequately assess the balance of benefits and harms of universal screening of children 18 to 30 months of age for ASD [86]. Pending additional evidence, we continue to suggest universal screening for ASD in children at 18 and 24 months of age. In our estimation, the potential benefits of early detection outweigh the potential harms of screening (eg, time, effort, anxiety). (See "Autism spectrum disorder: Surveillance and screening in primary care", section on 'Our screening recommendations'.)

PEDIATRIC IMMUNIZATIONS

Nonmedical vaccine exemptions and risk of measles and pertussis (March 2016)

Despite universal childhood vaccination programs in the United States, the incidence of measles and pertussis has increased since the early 2000s. A systematic review evaluated the association between vaccine refusal and measles or pertussis infection in the United States between 2000 and 2015 [87]. Nearly 60 percent of 1416 measles cases occurred in people who were not vaccinated against measles. Among the 574 unvaccinated cases who were old enough to have received measles vaccine, 71 percent refused it for nonmedical reasons (eg, religious or philosophic beliefs). Nonmedical exemptions also were prevalent among unvaccinated cases of pertussis (ranging from 59 to 93 percent in eight outbreaks). These findings confirm that nonmedical exemptions increase the risk of vaccine-preventable illness in the unvaccinated individual and, by reducing overall community immunity, increase the risk of illness in children too young to be vaccinated, people with medical contraindications to vaccination, and vaccinated people with waning immunity [88]. (See "Standard childhood vaccines: Parental hesitancy or refusal", section on 'For the individual'.)

PEDIATRIC NEONATOLOGY

WHO recommendations for infant prophylaxis to prevent mother-to-child HIV transmission (July 2016)

The World Health Organization (WHO) has updated its guidelines on the use of antiretroviral agents to manage and prevent HIV infection [89]. One major change from previous WHO statements involves post-exposure prophylaxis of infants born to HIV-infected mothers. The recommended regimen for infant prophylaxis now takes into account the infant's risk of infection, as determined by the timing of maternal infection and maternal antiretroviral treatment, in addition to the type of infant feeding; a two-drug regimen is recommended for high-risk infants. This recommendation was based, in part, on earlier data that demonstrated a lower HIV transmission rate with dual-agent rather than single-agent prophylaxis among infants born to mothers who had not received antiretroviral agents during pregnancy. (See "Prevention of mother-to-child HIV transmission in resource-limited settings", section on 'Infant antiretroviral use'.)

Neonatal phototherapy and potential increased risk of cancer (June 2016)

Phototherapy is used widely to treat neonatal hyperbilirubinemia and thought to be a relatively safe intervention, although concerns of an association with childhood cancer have been raised. Two recent studies have reinforced this uncertainty:

In a retrospective cohort study including almost 500,000 infants ≥35 weeks gestational age, the overall prevalence of childhood cancer was greater in children exposed to phototherapy compared with unexposed controls (25 versus 18 per 100,000 person-years) [90]. However, after controlling for confounding variables, the risks for overall cancer, nonlymphocytic leukemia, and liver cancer were similar for both groups.

In a study that linked birth and death certificate and hospital discharge data for infants born in California, infants with diagnosis codes for phototherapy were more likely to have a cancer diagnosis by one year of age than those without such codes (32.6 versus 21 per 100,000 patients) [91]. The risks for overall cancer, myeloid leukemia, and kidney cancer persisted after adjusting for confounders.

If phototherapy is a risk factor for childhood cancer, the effect appears to be no more than modest. Given this possibility, phototherapy should be prescribed judiciously. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Childhood cancer'.)

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