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)].
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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
E-cigarette use and use of combustible tobacco products (August 2015)
Studies have associated e-cigarette use with an increased risk of conventional cigarette smoking among youth. A new prospective study was conducted in 2530 ninth-grade students who had never used a combustible tobacco product and compared students who had ever used e-cigarettes with never users . Compared with never users, ever users of e-cigarettes were more likely to report use of any combustible tobacco product at both 6-month (31 versus 8 percent) and 12-month (25 versus 9 percent) follow-up. Additionally, after adjusting for other risk factors for smoking, baseline e-cigarette use was associated with a greater likelihood of use of any combustible tobacco product (OR 2.7), including conventional cigarettes, cigars, and hookahs. (See "E-cigarettes", section on 'Effect on smoking initiation among youth'.)
Cognitive-behavioral therapy for insomnia (August 2015)
Cognitive-behavioral therapy for insomnia (CBT-I) is a safe and effective alternative to medication in patients with chronic insomnia. A 2015 meta-analysis identified 20 randomized trials of CBT-I in over 1100 participants with chronic insomnia; CBT-I approaches incorporated at least three of the following: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation . Compared with inactive control conditions, CBT-I improved sleep on a variety of outcome measures, including sleep onset latency, wake time after sleep onset, and sleep efficiency. CBT-I is a particularly good option for patients who are more susceptible to side effects of medication (eg, older adults, patients with multiple medical comorbidities). (See "Treatment of insomnia", section on 'Cognitive behavioral therapy'.)
Platelet-rich plasma for acute muscle injury (July 2015)
Platelet-rich plasma (PRP) injections have been touted as an effective treatment for acute muscle and tendon injuries despite scant evidence from randomized trials. The results of a recent randomized trial of 90 professional athletes with acute, MRI-confirmed hamstring injury cast further doubt on the effectiveness of PRP. In this trial, athletes treated with a single PRP injection in addition to intensive physical therapy did not return to play any faster than athletes treated with intensive physical therapy alone . Re-injury rates were also similar. (See "Hamstring muscle and tendon injuries", section on 'PRP and other injections'.)
Menopausal hormone therapy and cardiovascular risk: Timing of exposure (June 2015)
Current evidence suggests that the use of menopausal hormone therapy (MHT) in the early menopausal years (<10 years from menopause) may not be associated with excess cardiovascular risk when compared with use in the later menopausal years. This has been referred to as the "timing hypothesis." Additional support for this hypothesis comes from a 2015 meta-analysis of 19 trials of oral (including the Womens Health Initiative), but not transdermal, MHT in over 40,000 postmenopausal women . A subgroup analysis in women who started MHT less than 10 years after menopause showed a lower risk of coronary heart disease (CHD) compared with placebo (RR 0.52; 8 fewer cases of heart disease per 1000 women treated/year) and a lower mortality rate (RR 0.70; 6 fewer deaths per 1000 women treated/year). However, there were important limitations in this analysis; when one methodologically flawed trial was removed, the beneficial effects on CHD and mortality were no longer significant (but no adverse effects were seen). These data provide additional evidence that oral MHT use in younger postmenopausal women is not associated with excess CHD risk. (See "Menopausal hormone therapy: Benefits and risks", section on 'Younger postmenopausal women'.)
US ACIP recommendations for serogroup B meningococcal vaccination (June 2015)
In late 2014 and early 2015, the US Food and Drug Administration approved two serogroup B meningococcal vaccines (Trumenba, MenB-FHbp and Bexsero, MenB-4C). In June 2015, the Advisory Committee on Immunization Practices (ACIP) issued recommendations for serogroup B meningococcal vaccine for high-risk individuals aged 10 years or older; these include individuals with persistent complement component deficiencies, individuals with anatomic or functional asplenia, microbiologists routinely exposed to N. meningitidis isolates, and individuals at increased risk because of a serogroup B meningococcal disease outbreak . These indications overlap with those for the quadrivalent meningococcal conjugate vaccine and are summarized in the table (table 1). Among patients with none of the above risk factors, the ACIP advises discussion between doctors and patients regarding vaccination against serogroup B meningococcus; routine vaccination has not been recommended . (See "Meningococcal vaccines", section on 'Use in United States'.)
Comparison of commercial weight loss programs in the United States (April 2015)
A comprehensive lifestyle intervention (combined diet, exercise, and behavioral treatment) is the most important strategy for weight management. Self-help or commercial weight loss programs incorporate varying degrees of behavioral modification strategies with dietary change. A systematic review of the major available programs in the United States reported outcomes based upon a variety of measures . Only two programs (Weight Watchers and Jenny Craig) reported 12-month outcomes. Compared with control groups that included education or education plus counseling, trials found an approximately 3 to 5 percent greater weight loss at 12 months for participants in the intervention arms. Longer-term outcomes are needed to better evaluate the effectiveness of other commercial programs. Commercial programs are an option for weight management of overweight or obese patients, with the recommendation that programs with clinically demonstrated efficacy be the first choice. (See "Obesity in adults: Behavioral therapy", section on 'Self-help or commercial weight loss programs'.)
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 . 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'.)
Early cardiovascular disease in youth with depressive and bipolar disorders (October 2015)
The American Heart Association recently proposed that major depression and bipolar disorder in adolescents be positioned alongside other pediatric diseases that are considered moderate risk conditions for early cardiovascular disease (CVD), which include chronic inflammatory diseases (eg, systemic lupus erythematosus), HIV infection, and nephrotic syndrome . There is growing evidence that major depression and bipolar disorder are associated with accelerated atherosclerosis and early CVD. In addition, traditional risk factors for CVD (eg, obesity, diabetes mellitus, sedentary lifestyle, and smoking) are more prevalent in youth with major depression and bipolar disorder. Although psychotropic medication may contribute to the elevated risk of cardiovascular disease, particularly in youths with bipolar disorder, it appears that the association between depression and cardiovascular disease is independent of medication effects. Management of youth with major depression and bipolar disorder should thus include monitoring and management of other CVD risk factors, including body mass index, blood pressure, lipids, and fasting glucose. (See "Diseases associated with atherosclerosis in childhood", section on 'Depressive and bipolar disorders'.)
Revised schedule for pneumococcal vaccination in older adults (September 2015)
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 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending the 13-valent pneumococcal conjugate vaccine (PCV13) for adults ≥65 years of age . In September 2015, the ACIP changed the recommended interval between administration of PCV13 and PPSV23 for immunocompetent adults ≥65 years of age from 6-12 months to ≥1 year to simplify the administration schedule (algorithm 1) . In patients who have already received PPSV23, at least 1 year should elapse before they are given PCV13. (See "Pneumococcal vaccination in adults", section on 'Schedule for dual vaccination'.)
PCSK9 antibodies for cardiovascular risk reduction (September 2015)
Monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9-abs) reduce LDL-cholesterol levels by as much as 70 percent. Randomized trials with small numbers of events and limited follow-up suggest that at least two of these agents, alirocumab and evolocumab, substantially reduce cardiovascular events and mortality when used for secondary prevention, both as monotherapy and in combination with statin therapy [12,13]. (See "Lipid lowering with drugs other than statins and fibrates", section on 'PCSK9 inhibitors'.)
PCSK9-abs are becoming available for clinical use. The agents require subcutaneous injection every two to four weeks and are very expensive. While awaiting greater experience with these agents, we would use them in situations where the expected reductions in cardiovascular events are likely to outweigh any as yet unknown adverse events from a new therapy. These include using them in combination with statin therapy in very high-risk patients such as those in the proposed NCEP guidelines (table 2), and as monotherapy in high-risk and very high-risk patients who are intolerant of statin therapy. (See "Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease", section on 'Stable CVD'.)
Light and moderate alcohol consumption and cancer risk (August 2015)
Alcohol use has been associated with increased risk for cancer, with heavy use being associated with the highest risk. A prospective cohort study of health professionals in the United States that included over 88,000 women and 47,000 men followed for 30 years found that compared with nondrinkers, light and moderate drinkers had a small but nonsignificant increase in cancer risk . However, in women who had never smoked, there was an increased risk of alcohol-related cancer (defined as colorectum, female breast, oral cavity, pharynx, larynx, liver and esophagus) even with one alcoholic drink a day, mainly driven by an increase in breast cancer. (See "Overview of the risks and benefits of alcohol consumption", section on 'Cancer'.)
Cardiovascular mortality and modifiable risk factors (August 2015)
Cardiovascular disease (CVD) remains the leading cause of death in the United States (US). Improved risk factor modification can decrease CVD mortality. In descriptive data from a nationally representative survey, five modifiable risk factors for CVD (elevated cholesterol, diabetes, hypertension, obesity, and smoking) accounted for one-half of CVD deaths in US adults aged 45 to 79 from 2009 to 2010 . The preventable fraction of CVD mortality associated with these risk factors was 54 percent for men and 50 percent for women. (See "Overview of primary prevention of coronary heart disease and stroke", section on 'Rationale'.)
Influenza vaccine recommendations for 2015-2016 influenza season (August 2015)
In August 2015, the Advisory Committee on Immunization Practices released recommendations for the prevention and control of influenza during the 2015-2016 influenza season in the United States. As in previous seasons, seasonal influenza vaccination is recommended for everyone ≥6 months of age . Changes for the 2015-2016 season include:
●Different influenza A H3N2 and influenza B (Yamagata lineage) antigens than were in the 2014-2015 vaccines
●A simplified dosing algorithm for children six months through eight years (algorithm 2)
●Availability of a quadrivalent intradermal vaccine for adults 18 through 64 years of age (table 3)
Reduced HPV vaccination rate among women who have sex with women (May 2015)
Prior research has suggested that women who have sex with women (WSW) may be less likely to initiate human papillomavirus (HPV) vaccination than their age-matched heterosexual peers. One possible reason for this discrepancy is that both WSW and their healthcare providers may erroneously believe that WSW are not at risk for HPV infection or cervical cancer. In one study of over 12,000 United States women from 2006 to 2010, of women who were aware of the HPV vaccine, only 8 percent of lesbian women had initiated vaccination compared with 28 percent of heterosexual women and 32 percent of bisexual women . This study highlights the need for healthcare providers to discuss HPV vaccination with all patients. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend vaccination for females and males ages 11 or 12 years of age, up to age 26. (See "Medical care of women who have sex with women", section on 'Prevention of sexually transmitted diseases'.)
Folate and cardiovascular prevention (May 2015)
Homocysteine reduction with B vitamin supplementation has not generally appeared to be beneficial in reducing cardiovascular risk. However, there have been concerns that most trials have not adequately assessed baseline folate intake in participants. A randomized trial of folic acid supplementation in Chinese adults with hypertension found a reduction in the risk of first stroke (2.7 versus 3.4 percent) . This trial was performed in patients with low folate levels and with very low rates of use of statins and antiplatelet agents, and there was some suggestion that the benefit was primarily in patients with the lowest baseline levels of folate. These results are consistent with an earlier meta-analysis of folic acid supplementation and stroke that found benefits in populations with no or partial fortification of food with folic acid, and that also found greater benefit in trials in patients with low use of statins . In patients coming from areas without dietary fortification, or who have diets that may have inadequate folate (eg, severe alcoholics), B-vitamin supplementation may be appropriate. (See "Overview of homocysteine", section on 'Supplementation in the general population'.)
The efficacy of an inactivated vaccine to prevent zoster (April 2015)
The live attenuated zoster vaccine reduces the risk of herpes zoster with a reported vaccine efficacy of 60 to 70 percent in adults 50 years and older, but it cannot be used in immunocompromised individuals and may have decreased efficacy in adults 70 years and older. A randomized, placebo-controlled trial evaluated the efficacy of HZ/su, an experimental recombinant inactivated zoster vaccine administered in two doses two months apart, among 15,411 adults 50 years and older . After three years of follow-up, the overall vaccine efficacy against herpes zoster was 97.2 percent (95% CI 93.7-99.0), and efficacy among adults 70 years and older was similar to that seen in adults between 50 and 69 years of age. (See "Prevention of varicella-zoster virus infection: Herpes zoster", section on 'Inactivated vaccines'.)
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 . 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 . 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'.)
ACP recommendations for behavioral health (September 2015)
The American College of Physicians (ACP) has issued a new position paper on integrating behavioral health evaluation into primary care. The ACP does not make specific recommendations about screening for depression. However, the ACP supports the integration of behavioral health care (including screening, diagnosis, brief treatment, and referral) into primary care, and encourages addressing behavioral health issues within the limits of available resources . This is consistent with our suggestion to screen adults for depression when staff-assisted supports are in place to ensure appropriate diagnosis, treatment and follow-up. (See "Screening for depression", section on 'United States'.)
Breast density and supplemental screening following mammography (May 2015)
Although multiple states in the United States have passed legislation requiring clinicians to inform women of increased breast density when found on mammography and the potential need for supplemental ultrasound screening, indications for supplemental ultrasound remain uncertain. A prospective cohort study, using data from the U.S. Breast Cancer Surveillance Consortium (BCSC), evaluated breast density and five-year breast cancer risk (by the BCSC risk model) as factors associated with interval cancer following a negative screening mammogram . A high interval cancer rate (invasive cancer occurring 12 months or less after a normal mammogram) was defined as more than 1 case per 1000 mammograms. Women with heterogeneously dense breasts and a five-year breast cancer risk of 2.5 percent or greater, and women with extremely dense breasts and a five-year risk of 1.67 percent or greater, had a high interval cancer risk and were at highest risk of advanced stage disease. However, interval cancer rates were not found to be high for more than 50 percent of women with heterogeneously or extremely dense breasts. Combining increased breast density with an increased five-year risk could identify subsets of women who would be more likely to benefit from supplemental screening. (See "Breast imaging for cancer screening: Mammography and ultrasonography", section on 'Supplemental screening'.)
Interval for follow-up after benign breast biopsy (April 2015)
The appropriate interval for follow-up of patients with a benign biopsy of a palpable breast mass or radiographic breast abnormality is controversial. A study using the Breast Cancer Surveillance Consortium registry compared short-interval (3 to 8 months) with longer-interval (9 to 18 months) follow-up breast imaging screening after 17,631 benign core breast biopsies . Similar rates of cancer were later detected with no significant differences in stage, tumor size, or nodal status for the short-interval and longer-interval follow-up groups. In this study, it was not determined if the initial benign biopsies in women with subsequently detected cancers represented false negatives. Short interval follow-up is likely unnecessary in women with benign breast biopsy, but if there is any uncertainty about the biopsy results, we follow-up after six months. (See "Clinical manifestations and diagnosis of a palpable breast mass", section on 'Diagnosis'.)
ADULT CARDIOVASCULAR MEDICINE
Modified Valsalva maneuver for treatment of hemodynamically stable supraventricular tachycardia (September 2015)
For both diagnostic and therapeutic purposes, the Valsalva maneuver is commonly used in patients with suspected supraventricular tachycardia (SVT). In a randomized trial of vagal maneuvers for the treatment of hemodynamically stable SVT, patients were assigned to perform the standard Valsalva maneuver (strain generating 40 mmHg pressure for 15 seconds while in a semirecumbent position) with or without supine repositioning and passive leg raise for 15 seconds following the strain phase . Patients performing the modified Valsalva maneuver with supine repositioning and passive leg raise were significantly more likely to have restoration of sinus rhythm at one minute. For patients with hemodynamically stable SVT who are able to effectively perform the maneuver, we recommend the modified Valsalva maneuver as the initial treatment. (See "Atrioventricular nodal reentrant tachycardia", section on 'Stable patient'.)
Angiotensin receptor-neprilysin inhibitor for heart failure with reduced ejection fraction (July 2015)
Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved in the United States by the Food and Drug Administration for use in patients with chronic New York Heart Association (NYHA) functional Class II to IV heart failure with reduced ejection fraction (HFrEF) . In a randomized trial, sacubitril-valsartan reduced mortality and morbidity compared with angiotensin converting enzyme (ACE) inhibitor therapy, when used in combination with other standard heart failure therapies. Given the limited experience with sacubitril-valsartan at the present time, we suggest reserving its use, as a replacement for ACE inhibitor therapy, in patients with HFrEF with no improvement in NYHA class or worsening symptoms on optimally titrated medical therapy including an ACE inhibitor. This recommendation is likely to evolve with time as more data become available and experience with sacubitril-valsartan develops. (See "Use of angiotensin II receptor blocker and neprilysin inhibitor in heart failure with reduced ejection fraction", section on 'Indication'.)
Coronary artery embolism as the cause of acute MI (July 2015)
Atherosclerotic coronary artery obstruction is the cause of myocardial infarction (MI) in the overwhelming majority of patients. However, no obstructive coronary atherosclerosis is found in approximately 5 percent of patients; multiple possible causes have been identified. The relationship between MI and coronary artery embolism (CE) due to atrial fibrillation (AF) was evaluated in a study of 1776 patients who presented with an acute MI . The prevalence of CE was about 3 percent and atrial fibrillation was the most likely cause in three quarters of these. In patients with acute MI who do not have obstructive atherosclerotic coronary artery disease as the likely cause, undiagnosed or untreated atrial fibrillation with CE may be the explanation. (See "Myocardial infarction with no obstructive coronary atherosclerosis", section on 'Coronary artery embolism'.)
Optimal dose of aspirin after acute MI with stenting (July 2015)
The optimal dose of aspirin for patients with acute myocardial infarction (MI) who undergo stenting is not known. The TRANSLATE-ACS study evaluated outcomes in a non-randomized series of 10,123 patients who were discharged on dual antiplatelet therapy that included either 325 or 81 mg of aspirin . At six months after discharge, the higher dose of aspirin was associated with an increased rate of minor bleeding not requiring hospitalization, although the rate of major adverse events was similar. We suggest that MI patients undergoing stenting be discharged on 75 to 81 mg of aspirin rather than higher doses. (See "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Aspirin for all patients'.)
Ivabradine for rate control in heart failure with reduced ejection fraction (July 2015)
Ivabradine slows the sinus rate through inhibition of the f-channels. For patients with chronic stable heart failure with left ventricular ejection fraction (LVEF) ≤35 percent, in sinus rhythm with a resting heart rate ≥70 beats per minute (bpm), and who are either on a maximum tolerated dose of a beta blocker or who have a contraindication to beta blocker use, we suggest treatment with ivabradine, as approved in the United States  and previously approved in Europe. In such patients, ivabradine has been shown to reduce the risk of hospitalization for worsening heart failure. (See "Use of beta blockers and ivabradine in heart failure with reduced ejection fraction", section on 'Our recommendations'.)
Oxygen not helpful in normoxic STEMI patients (June 2015)
Small studies have raised the possibility of harm from supplemental oxygen in patients with ST-elevation myocardial infarction (STEMI). In the AVOID study, 441 normoxic patients with confirmed STEMI were randomly assigned to either supplemental oxygen (8 L/min) or no oxygen . The trial showed no improvement in the primary end point of a diminution in infarct size with oxygen and perhaps evidence of a larger infarct. For STEMI patients who are not hypoxic, we suggest not administering supplemental oxygen. (See "Overview of the acute management of ST elevation myocardial infarction", section on 'Oxygen'.)
Duration of dual antiplatelet therapy after coronary stenting (June 2015)
The optimal duration of dual antiplatelet therapy (DAPT) for patients who have received a drug-eluting intracoronary stent is not known. All randomized trials have found an increased rate of major bleeding and a lower rate of myocardial infarction with longer therapy. A 2015 meta-analysis confirmed a finding of an increase in all-cause mortality seen in some of the trials, although the magnitude of this increase was small . For patients who have tolerated 12 months of DAPT, we suggest continuing it for at least an additional 18 months. (See "Antiplatelet therapy after coronary artery stenting", section on 'Drug-eluting stents'.)
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) . 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'.)
ADULT ENDOCRINOLOGY AND DIABETES
Empagliflozin in diabetic individuals with overt cardiovascular disease (September 2015)
The cardiovascular effects of diabetes drugs have been evaluated in a growing number of trials. In a trial designed to evaluate the sodium-glucose co-transporter 2 (SGLT-2) inhibitor empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease (CVD), 7028 patients were randomly assigned to empagliflozin or placebo once daily . The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents, and approximately half in each group were taking insulin.
After three years, the primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients assigned to empagliflozin than to placebo (10.5 versus 12.1 percent), driven by a significant reduction in risk of death from cardiovascular causes (3.7 versus 5.9 percent). The difference in glycemia between the groups was minimal (glycated hemoglobin [A1C] 7.8 versus 8.2 percent), suggesting that extra-glycemic effects of the drug were responsible for the CVD outcome. Whether empagliflozin or other SGLT-2 inhibitors will have similar CVD effects in persons with type 2 diabetes who do not have overt CVD is unknown. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)
Bariatric surgery for diabetic patients and glycemic control (September 2015)
Bariatric surgical treatment of obese patients with diabetes results in significant sustained weight loss (20 to 30 percent after one to two years) and, in parallel, large improvements in blood glucose control. However, there are few data on long-term success rates in maintaining weight loss and glucose control. In a report of five-year outcomes (53 patients) from a randomized trial evaluating gastric bypass, biliopancreatic diversion, or medical therapy (pharmacologic therapy, education, lifestyle modification) in 60 patients with obesity and type 2 diabetes, diabetes remission (A1C <6.5 percent without diabetes medication) was maintained in only 56 percent of patients in the surgical groups who had experienced remission at two years . Compared with the medical group, patients treated surgically had significantly lower diabetes and cardiovascular medication use, serum total and LDL cholesterol, and weight, although weight regain occurred in both surgical groups (+6.09 and +4.56 kg, respectively). The study was not powered to assess long-term diabetes complications. Longer-term follow-up of microvascular and macrovascular complications and mortality are required before laparoscopic banding or other bariatric surgery procedures can be routinely recommended for the treatment of persistent hyperglycemia in obesity-related type 2 diabetes. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Surgical treatment of obesity'.)
FTO variant and obesity (September 2015)
Large genome wide association studies have demonstrated that variants in the FTO gene have the strongest association with obesity risk in the general population, but the mechanism of the association has been unclear. However, a nonocoding causal variant in FTO has now been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) with a fivefold decrease in mitochondrial thermogenesis . When the effect of the variant was blocked in genetically engineered mice, thermogenesis increased and weight gain did not occur, despite eating a high-fat diet. Blocking the gene's effect in human adipocytes also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. (See "Pathogenesis of obesity", section on 'FTO variants'.)
SGLT2 inhibitors may predispose to DKA (July 2015)
Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. “Euglycemic” (usually meaning plasma glucose <250 mg/dL) diabetic ketoacidosis (DKA) has been reported in patients with type 2 diabetes taking SGLT2 inhibitors [37,38]. The absence of substantial hyperglycemia delayed recognition of DKA by both the patients and the clinicians. Thus, serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. A warning about SGLT2 inhibitors and ketoacidosis was issued by the US Food and Drug Administration in May 2015. Given the absence of long-term efficacy and safety data, we do not recommend SGLT2 inhibitors for routine use in patients with type 2 diabetes. In addition, off-label use in type 1 diabetes is discouraged in the absence of sufficient safety data. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'SGLT2 inhibitors'.)
Liraglutide for the treatment of obesity (July 2015)
Along with diet, exercise, and behavior modification, drug therapy may be a helpful component of treatment for select patients who are overweight or obese. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, used for the treatment of type 2 diabetes, and can promote weight loss in patients with diabetes, as well as those without diabetes.
●In a randomized trial in nondiabetic patients who had a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with dyslipidemia and/or hypertension, liraglutide 3 mg once daily, compared with placebo, resulted in greater mean weight loss (-8.0 versus -2.6 kg with placebo) . In addition, cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life improved modestly. Gastrointestinal side effects transiently affected at least 40 percent of the liraglutide group and were the most common reason for withdrawal (6.4 percent). Liraglutide is an option for select overweight or obese patients, although gastrointestinal side effects (nausea, vomiting) and the need for a daily injection may limit the use of this drug. (See "Obesity in adults: Drug therapy", section on 'Liraglutide'.)
●In a trial designed specifically to evaluate the effect of liraglutide on weight loss in overweight or obese patients with type 2 diabetes (mean weight 106 kg), liraglutide, compared with placebo, resulted in greater mean weight loss (-6.4 kg and -5.0 kg for liraglutide 3 mg and 1.8 mg, respectively, versus -2.2 kg for placebo) . Treatment with liraglutide was associated with better glycemic control, a reduction in the use of oral hypoglycemic agents, and a reduction in systolic blood pressure. Although liraglutide is not considered as initial therapy for the majority of patients with type 2 diabetes, it is an option for select overweight or obese patients with type 2 diabetes who fail initial therapy with lifestyle intervention and metformin. (See "Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Weight loss'.)
DPP-4 inhibitors for diabetes and cardiovascular safety (June 2015)
A number of trials have evaluated the cardiovascular effects of DPP-4 inhibitors. In a recent large trial, 14,735 patients with type 2 diabetes and established cardiovascular disease were randomly assigned to sitagliptin or placebo, in addition to other diabetes medications (predominantly metformin, sulfonylurea, insulin) . After a median follow-up of three years, there was no difference in the primary composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina), individual components of the composite, or hospitalization rate for heart failure (3.1 percent in each group). Although these data are reassuring, longer-term clinical trials are needed to definitively assess the cardiovascular safety of DPP-4 inhibitors in patients with heart disease. In addition, there are no data on cardiovascular safety in lower-risk patients. With only modest glucose-lowering effectiveness and relative expense, we do not consider DPP-4 inhibitors as options for initial therapy in the majority of patients with type 2 diabetes. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
ADULT HEMATOLOGY AND ONCOLOGY
Bridging anticoagulation in patients who require warfarin interruption for surgery (July 2015)
Perioperative management of a patient receiving an anticoagulant is challenging because the risks of bleeding and thromboembolism are both increased. Not all patients require anticoagulant interruption. For those who do require interruption of their anticoagulant, the risks and benefits of bridging (use of a short-acting parenteral agent, typically a low molecular weight [LMW] heparin) have been unclear. The BRIDGE trial randomly assigned patients with atrial fibrillation to receive the LMW heparin dalteparin or placebo during warfarin interruption for surgery or an invasive procedure . The risk of thromboembolism was similar in those who received dalteparin or placebo for bridging. However, patients bridged with dalteparin had a greater risk of bleeding. As a result of the BRIDGE trial, we suggest not using bridging for most individuals who require warfarin interruption. We continue to suggest bridging in certain high-risk individuals, including those with a mechanical mitral valve, thromboembolic event within the previous 12 weeks, atrial fibrillation and very high risk of stroke, recent coronary stenting, or previous thromboembolism during interruption of chronic anticoagulation. (See "Perioperative management of patients receiving anticoagulants", section on 'Whether to use bridging'.)
Weak association between citrus fruit and melanoma (July 2015)
An analysis of data from over 100,000 individuals participating in the Nurse’s Health Study found a modest 36 percent increase in melanoma risk associated with high dietary intake of citrus fruit or juice, after adjusting for known risk factors for melanoma, such as family history of melanoma, phenotypic characteristics, number of nevi, and lifetime number of blistering sunburns . A potential explanation for this association is that citrus fruits are a source of psoralens, chemical compounds present in plants known to be photosensitizers. However, the results of this study need further confirmation, because, given the small increase in risk, residual confounding cannot be excluded. In the meanwhile, changes in dietary advice to the public are not warranted. (See "Risk factors for the development of melanoma", section on 'Other proposed risk factors'.)
Practice tool for managing direct oral anticoagulants (July 2015)
The direct oral anticoagulants ([DOACs]; dabigatran, rivaroxaban, apixaban, edoxaban) generally are used without routine laboratory monitoring of coagulation times; this lack of monitoring requirement is considered a major advantage over vitamin K antagonists. However, the DOACs have short half-lives, and one or two missed doses can be sufficient to eliminate their anticoagulant effect. A practice tool has been published to help clinicians ensure that patients are taking their DOAC correctly and are minimizing risks of thromboembolism and bleeding . Counseling strategies are focused on minimizing gaps in therapy and avoiding medication interactions. Monitoring of renal function and treatment of hypertension are also emphasized. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Comparison with heparin and warfarin'.)
ADULT INFECTIOUS DISEASE
Adjunctive glucocorticoids for adults with severe community-acquired pneumonia (August 2015)
For hospitalized patients with community-acquired pneumonia (CAP), glucocorticoids as adjunctive therapy to antibiotics have the potential to reduce the inflammatory response and decrease morbidity. A 2015 meta-analysis of randomized trials that included hospitalized patients with CAP suggested a modest mortality benefit for adjunctive glucocorticoids . A reduction in all-cause mortality was of borderline statistical significance (relative risk [RR] 0.67, 95% CI 0.45-1.01; risk difference 2.8 percent). Rates of mechanical ventilation and acute respiratory distress syndrome were decreased, as were time to clinical stability and duration of hospitalization; rates of hyperglycemia requiring treatment increased.
Clinicians should make the decision whether or not to give glucocorticoids on a case-by-case basis, especially in patients with an elevated risk of adverse effects. We suggest adjunctive glucocorticoids for most hospitalized patients with CAP who have a Pneumonia Severity Index score of IV or V (calculator 1) or a CURB-65 score ≥2 (calculator 2). Limited evidence suggests that infections caused by certain pathogens (eg, influenza virus, Aspergillus spp) may be associated with worse outcomes in the setting of glucocorticoid use [46,47]; given these concerns, we avoid adjunctive glucocorticoids if one of these pathogens is detected. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Glucocorticoids'.)
Causes of community-acquired pneumonia in adults in the United States (July 2015)
As molecular tests have become more widely available, viruses are being detected with increasing frequency in patients with community-acquired pneumonia (CAP). In the Etiology of Pneumonia in the Community (EPIC) study, an active Centers for Disease Control and Prevention (CDC) surveillance study of adults requiring hospitalization for CAP, one or more viruses were detected in 23 percent of cases, bacteria in 11 percent, bacteria and viruses in 3 percent, and fungi or mycobacteria in 1 percent; an etiology was not identified in 62 percent of cases . The most commonly identified organisms were rhinovirus (in 9 percent), influenza virus (in 6 percent), and S. pneumoniae (in 5 percent). In a related study, detection of rhinovirus was associated with CAP in adults, but not in children . These results add to accumulating evidence that rhinovirus is likely to play a role in CAP in adults. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Rhinovirus' and "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Microbiologic diagnosis'.)
Repeat testing for women treated for trichomoniasis (July 2015)
The risk of repeat infection following treatment for a sexually transmitted infection (STI) is high. In the United States, reinfection with Trichomonas vaginalis has been reported to occur in up to 17 percent of women following treatment for an initial infection. The 2015 Centers for Disease Control and Prevention (CDC) guidelines on the management of STIs recommend that women treated for confirmed T. vaginalis infection undergo repeat testing within three months of treatment, regardless of partner treatment status . Prior guidelines had only listed retesting as a consideration. The preferred diagnostic test for repeat testing is a nucleic acid amplification test (NAAT) on a vaginal swab, which can be performed as soon as two weeks after treatment. Data are insufficient to support retesting men. (See "Trichomoniasis", section on 'Follow-up'.)
Updated CDC guidelines on the management of sexually transmitted infections (June 2015)
The US Centers for Disease Control and Prevention (CDC) updated its guidelines on the management of sexually transmitted infections in June 2015 . Major revisions include a lower threshold for the diagnosis of urethritis based on microscopy of a urethral specimen, a new emphasis on the role of Mycoplasma genitalium in persistent urethritis and cervicitis, preference for nucleic acid amplification-based testing for the diagnosis of Trichomonas vaginalis, and a recommendation to retest women after treatment for T. vaginalis to evaluate for reinfection. New screening recommendations include annual hepatitis C virus (HCV) testing for HIV-infected men who have sex with men and T. vaginalis testing for HIV-infected women annually and when pregnant. (See "Urethritis in adult men", section on 'Diagnostic criteria' and "Mycoplasma genitalium infection in men and women", section on 'Nongonococcal urethritis' and "Trichomoniasis", section on 'Follow-up' and "Primary care of the HIV-infected adult", section on 'Sexually transmitted infections'.)
Prevalence and clinical presentation of Borrelia miyamotoi infection (June 2015)
Borrelia miyamotoi is an emerging zoonotic pathogen that is transmitted by the same genus of ticks (eg, Ixodes scapularis, Ixodes pacificus) that transmits Borrelia burgdorferi (the agent of Lyme disease), Anaplasma phagocytophilum, and Babesia species. In one case series, B. miyamotoi was identified using polymerase chain reaction (PCR) in approximately 1 percent of specimens from 11,515 patients in the northeastern United States who presented with an acute febrile episode from April through November in 2013 and 2014 . Clinical information was available for 51 patients with B. miyamotoi infection; the majority had marked headache, myalgia, arthralgia, malaise, and/or fatigue, and 24 percent were hospitalized. Diagnostic testing is not widely available, but doxycycline, which is used to treat many other tick-borne infections, is also effective against B. miyamotoi. (See "Borrelia miyamotoi infection", section on 'Clinical manifestations'.)
Antimicrobial-resistant Shigella infections in the United States (June 2015)
Antimicrobial resistance in Shigella is an increasing problem in the United States. Fluoroquinolones are typically the antibiotic class of choice in adults, and azithromycin is often used if fluoroquinolone resistance is suspected or documented. Clusters of ciprofloxacin-resistant cases, likely introduced by international travelers with subsequent domestic spread, have been reported throughout the country, and isolates with decreased susceptibility to azithromycin have caused outbreaks and sporadic cases, predominantly among men who have sex with men (MSM) [53,54]. Scattered infections with extremely drug-resistant isolates that are ciprofloxacin-resistant and have decreased susceptibility to azithromycin have also been reported . These reports highlight the importance of obtaining susceptibility testing to ensure adequate efficacy of the chosen antimicrobial when managing shigellosis and emphasizing prevention measures, primarily hygiene practices around food preparation or consumption and oral or anal sex. (See "Shigella infection: Treatment and prevention in adults", section on 'Antimicrobial resistance' and "Shigella infection: Treatment and prevention in children", section on 'Antibiotic resistance'.)
Persistence of Ebola virus in bodily fluids (May 2015)
Among survivors of the 2014-2015 Ebola outbreak in West Africa, infectious virus or viral RNA has been detected from several sites (eg, urine, semen, and aqueous humor) even after it is no longer detected in blood [56-58]. Although transmission from persistent virus at these sites is possible, the risk of transmission is not well established. As an example, a patient in West Africa had detectable viral RNA in his semen 199 days after symptom onset. There was apparent transmission of Ebola virus to one, but not another, of his sexual contacts. To prevent sexual transmission of Ebola virus, the Centers for Disease Control and World Health Organization suggest Ebola survivors refrain from all sexual activity (oral, anal, vaginal) until more information on the persistence of infectious virus in convalescent patients becomes available; condoms should be used if abstinence is not possible [59,60]. (See "Epidemiology and pathogenesis of Ebola virus disease", section on 'Risk of transmission through different body fluids'.)
Trends in infective endocarditis incidence in the United States (May 2015)
The epidemiology of infective endocarditis (IE) has changed over time because of changes in the prevalence of risk factors, as well as improved diagnostic tools and management. A study using the Nationwide Inpatient Sample database, which included 457,052 hospitalizations for IE in the United States between 2000 and 2011, found a steady increase in IE incidence over this time . The trends in hospitalization rates overall from 2000 to 2007 and from 2008 to 2011 were not significantly different, but there was a steeper increase in hospitalization rates for streptococcal IE, specifically, after 2007. It has been postulated that this reflects reduced antimicrobial IE prophylaxis after the American College of Cardiology/American Heart Association (ACC/AHA) recommended a narrower range of indications for prophylaxis in 2007. However, in the absence of controlled data, a causal connection is uncertain. Given the available evidence, we continue to recommend an approach to IE prophylaxis consistent with the ACC/AHA guidelines. (See "Epidemiology, risk factors, and microbiology of infective endocarditis", section on 'Epidemiology' and "Antimicrobial prophylaxis for bacterial endocarditis", section on 'Trends in endocarditis incidence'.)
Ocular syphilis in the United States (April 2015)
Ocular syphilis, a potentially sight-threatening form of neurosyphilis, has been reported more frequently among HIV-infected patients compared with those without HIV. It can occur at any time after initial infection and may be associated with rash. Ocular findings typically include uveitis or optic neuritis, and the diagnosis is supported by a reactive serologic test. In the United States, an outbreak of ocular syphilis has been reported in California and Washington since December 2014; the majority of cases were among HIV-infected men who have sex with men, and several cases resulted in blindness . (See "Epidemiology, clinical presentation, and diagnosis of syphilis in the HIV-infected patient", section on 'Neurosyphilis'.)
ADULT NEPHROLOGY AND HYPERTENSION
SPRINT trial on goal blood pressure halted early (September 2015)
Goal blood pressure in most hypertensive patients is <140/90 mmHg. The potential benefit of lowering the systolic blood pressure goal to <120 mmHg (compared with <140 mmHg) in nondiabetic older adults with risk factors for cardiovascular disease or with chronic kidney disease has been evaluated in the Systolic Blood Pressure Intervention Trial (SPRINT), which was halted early for benefit in September 2015 . However, the full results are not yet available and the clinical implications of this trial have not been determined. Thus, for now, our goal blood pressure recommendations remain the same. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Blood pressure goal'.)
Chlorthalidone and indapamide for hypertension treatment (July 2015)
Two meta-analyses compared thiazide-like diuretics (chlorthalidone and indapamide) with hydrochlorothiazide for the treatment of hypertension.
●In a meta-analysis of 14 trials that compared the blood pressure reduction with one of three dose levels of hydrochlorothiazide (low, intermediate, high) to a corresponding dose level of one of the thiazide-like diuretics, systolic pressure reduction was greater with chlorthalidone and indapamide (by 3.6 and 5.1 mmHg, respectively) .
●In a multiple-treatment (network) meta-analysis of 21 trials that indirectly compared thiazide-type diuretics (such as hydrochlorothiazide) with thiazide-like diuretics (such as chlorthalidone) by evaluating their efficacy against placebo or common comparator drugs, thiazide-like diuretics significantly lowered the relative risk of cardiovascular events by 12 percent and heart failure by 21 percent .
If a diuretic is chosen for treatment of hypertension, we suggest chlorthalidone or indapamide rather than hydrochlorothiazide.
Combination renin-angiotensin system inhibition in diabetic patients (June 2015)
Several randomized trials that directly compared dual versus single renin-angiotensin system inhibition in diabetic patients found that dual therapy produced no benefit and an increase in adverse effects. Findings are similar in a subsequent network meta-analysis . In this analysis in patients with diabetes and hypertension, dual therapy with an angiotensin-converting enzyme (ACE) inhibitor plus an angiotensin II receptor blocker (ARB) was superior to placebo in preventing end-stage renal disease, but monotherapy with either an ACE inhibitor or an ARB, also compared with placebo, produced similar benefits while dual therapy produced more adverse effects. Combination renin-angiotensin system inhibition with an ACE inhibitor and ARB or direct renin inhibitor is not recommended in diabetic patients. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Avoid combination renin-angiotensin system inhibition'.)
ADULT NEUROLOGY AND PSYCHIATRY
Mindfulness-based stress reduction for PTSD (August 2015)
Mindfulness-based stress reduction teaches patients to attend to the present moment in a nonjudgmental, accepting manner. A recent clinical trial in patients with posttraumatic stress disorder (PTSD) compared mindfulness-based stress reduction with present-centered group therapy, an active control . After nine weeks of treatment and two months of follow-up, participants in the mindfulness group were more likely to show clinically significant improvement in PTSD symptoms compared with control group participants. The two groups did not differ significantly in the proportion of patients who continued to meet diagnostic criteria for PTSD. Exposure-based cognitive behavioral therapy is first-line treatment for PTSD, but with further study, mindfulness-based stress reduction may provide an effective alternative for the significant proportion of patients who do not accept exposure therapy or do not respond to the treatment. (See "Psychotherapy for posttraumatic stress disorder in adults", section on 'Mindfulness-based stress reduction'.)
Limited improvement in negative symptoms in schizophrenia drug trials (June 2015)
Antipsychotic medications reduce the severity of positive symptoms in schizophrenia, such as hallucinations, delusions, and suspiciousness. Neither antipsychotic nor other medications have demonstrated comparable efficacy in the treatment of negative symptoms of the disorder, which include decreased expressiveness, apathy, flat affect, and a lack of energy. A recent meta-analysis of more than 12,000 patients with schizophrenia in over 160 randomized trials found second-generation antipsychotics, antidepressants, glutamatergic agents, and medication combinations to produce small reductions in negative symptoms compared with placebo, but not first-generation antipsychotics nor brain stimulation . None of the beneficial medication effects were considered to be of a clinically significant magnitude. Clinical trials continue to test other medications as well as psychosocial interventions in the treatment of negative symptoms.(See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment", section on 'Drug efficacy'.)
Amyloid PET imaging in adults with and without dementia (May 2015)
The clinical utility of amyloid positron emission tomography (PET) imaging in the evaluation of patients with cognitive impairment or dementia is uncertain, in part because beta-amyloid can be demonstrated in the brains of adults with normal cognition as well as in those with clinical Alzheimer disease (AD). In a meta-analysis of 55 studies of amyloid PET in adults without dementia (n = 8694), the prevalence of a positive amyloid PET scan increased with age, ranging from 10 percent in 50-year-olds with normal cognition to 44 percent in 90-year-olds with normal cognition . By contrast, among individuals with a clinical diagnosis of AD, the prevalence of a positive amyloid PET scan decreased with advancing age, ranging from 93 percent in 50-year-olds to 79 percent in 90-year-olds . Although several amyloid PET tracers have been approved by regulatory bodies, their high cost, in addition to their low specificity as stand-alone tests, have thus far limited use beyond research settings. (See "Neuroimaging studies in the evaluation of dementia", section on 'Indications for functional and molecular imaging'.)
Late-onset generalized anxiety disorder (April 2015)
Generalized anxiety disorder (GAD) is typically thought of as having an early onset, rarely first presenting in older adults. A recent, prospective study of a large, representative sample of French adults aged 65 years and over, who did not meet criteria for GAD at baseline, found the disorder to have an incidence of 8.4 percent over the subsequent 12-year period . In 80 percent of cases, the occurrence was the first episode of GAD. Predictors of incident GAD included being female, poverty, recent adverse life events, chronic physical or mental illness, and parental/familial factors. Increased awareness and recognition of late-onset GAD would enable more patients to receive effective treatments for the disorder, including cognitive behavioral therapy and selective serotonin reuptake inhibitors. (See "Generalized anxiety disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Course'.)
Extended anticoagulation for pulmonary embolism (July 2015)
Patients with unprovoked pulmonary embolism (PE) are at high risk of recurrence once anticoagulation is discontinued. Whether anticoagulation beyond a conventional course is beneficial was investigated in a randomized trial of 371 adult patients with a first episode of symptomatic unprovoked PE who had completed six months of warfarin therapy . Rates of recurrent thrombosis were seven times higher in patients treated with placebo compared with those who continued anticoagulant therapy. However, rates of major bleeding were higher with extended anticoagulation, and once discontinued, the benefit of reduced recurrence was not maintained. These results reflect similar data derived from patients with deep venous thrombosis treated with extended anticoagulant therapy. Clinicians should continue to evaluate patients with unprovoked venous thromboembolism on an individual basis and weigh the benefits of extended anticoagulation against the risk of major bleeding. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Recurrence with and without anticoagulation'.)
Limited occult cancer screening for venous thromboembolism (June 2015)
Occult cancer is associated with venous thromboembolism (VTE). However, evidence to support a specific evaluation strategy is limited. In a randomized trial of 854 patients with a first unprovoked episode of VTE, a limited strategy for the evaluation of cancer (basic laboratory testing, chest radiography, and breast, cervical, and prostate cancer screening) was compared with a more comprehensive strategy (the limited strategy plus CT of the abdomen and pelvis) . Both strategies identified a low incidence of cancer (approximately 4 percent) and cancer-related mortality at one year was low (1 percent) in both groups. Thus, the addition of CT of the abdomen and pelvis did not improve cancer detection, and the study supports our practice of adopting a limited approach to evaluation in patients with a first episode of unprovoked VTE. (See "Evaluating patients with established venous thromboembolism for acquired and inherited risk factors", section on 'First episode of uncomplicated unprovoked VTE'.)
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 . 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'.)
Arthroscopic surgery for knee osteoarthritis (June 2015)
Arthroscopic knee surgery, including partial meniscectomy and/or debridement, has been widely used as a therapeutic intervention for symptomatic osteoarthritis of the knee, with or without a meniscal tear, although efficacy data are lacking. A meta-analysis identified nine randomized trials comparing arthroscopic knee surgery (involving partial meniscectomy, debridement, or both) with non-surgical treatments in middle-aged and older patients with knee pain, with or without radiographic evidence of knee osteoarthritis . There was a clinically insignificant difference in pain in favor of arthroscopic knee surgery at three and six months of follow-up, but not at later times points up to 24 months. There was no significant benefit of knee arthroscopy on physical function. Adverse events after knee arthroscopy included deep venous thrombosis (4 per 1000 arthroscopies), infection, pulmonary embolism, and death. These findings support the lack of clinical efficacy of arthroscopic knee surgery in the treatment of knee pain from osteoarthritis. (See "Overview of surgical therapy of knee and hip osteoarthritis", section on 'Osteoarthritis plus a meniscal tear'.)
Medication approved for low sexual desire in women (August 2015)
Flibanserin is the first and currently only drug approved by the US Food and Drug Administration (FDA) for female sexual dysfunction . Daily use results in modest increases in the frequency of sexually satisfying events and sexual desire. The clinical role of flibanserin may be limited by the need for daily dosing, common adverse effects (eg, somnolence, dizziness), and by safety concerns or lack of safety data regarding combining flibanserin with alcohol or certain medications (eg, fluconazole, CYP3A4 inhibitors, antidepressants). (See "Sexual dysfunction in women: Management", section on 'Flibanserin'.)
Safety concerns regarding hysteroscopic sterilization (July 2015)
Safety concerns have been raised about female sterilization via hysteroscopic placement of micro-inserts into the fallopian tubes. A prospective study of this procedure reported that, at five years, up to 38 percent of women reported recurrent menstrual irregularities and up to 5 percent reported recurrent pelvic pain . Between 2002 and 2015, the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database received 5093 adverse effects reports related to this device, including over 4700 related to menstrual abnormalities or pelvic pain . In September 2015, the FDA will convene a meeting of the Obstetrics and Gynecology Devices Panel to review the safety and effectiveness of hysteroscopic sterilization. (See "Hysteroscopic sterilization", section on 'FDA panel'.)
Improving uptake of long-acting reversible contraceptives (July 2015)
Long-acting reversible contraceptives (LARC), which include implants and intrauterine devices, are the most effective reversible methods to prevent pregnancy. Interventions that increase LARC use lower the rate of unintended pregnancy. In a trial of 1500 women who were randomly assigned to receive either standardized counseling for LARC or routine contraceptive counseling, standardized counseling resulted in increased LARC use and a reduction in unintended pregnancies (8 versus 15 percent) . Introduction of affordable LARC methods in the state of Colorado from 2009 to 2013 was associated with an approximately 40 percent reduction in teen birth and abortion rates compared with previous years . These data add further support to our suggestion to use LARC for women who desire reversible contraception. (See "Overview of contraception", section on 'Effectiveness'.)
Frozen donor oocyte use impacts live birth rate (August 2015)
Use of donor oocytes (eggs) in assisted reproductive technology has allowed women unable to conceive with their own eggs the opportunity to achieve pregnancy. The use of frozen oocytes is more convenient and less costly compared with fresh oocytes because the donor and recipient don't have to be hormonally synchronized and frozen eggs can be shipped anywhere. Although initial studies reported equivalent pregnancy and live birth rates for donor egg transfers, a study of over 11,000 oocyte donation cycles, including 20 percent using frozen eggs, reported the live birth rate per transfer for frozen donor oocytes was lower than the live birth rate for fresh donor oocytes (47 versus 56 percent) . Despite the possible discrepancy in live birth rate, the improved efficiency and lower cost of cryopreserved donor oocytes makes their use a reasonable and attractive option. (See "Management of infertility and pregnancy in women of advanced age", section on 'Oocyte or embryo donation'.)
Prescription medications during pregnancy (August 2015)
Concerns have been raised regarding the frequency with which medication is prescribed during pregnancy, especially for those drugs that may have adverse outcomes for the mother or her fetus. In a study of over one million pregnant women in the United States Medicaid program, nearly 40 percent were prescribed a potentially harmful medication (category D, most commonly codeine and hydrocodone) and 5 percent were prescribed a medication contraindicated during pregnancy (category X, most commonly hormonal contraceptives that were prescribed prior to the diagnosis of pregnancy) . Overall, 83 percent were dispensed at least one medication of any kind (most commonly antibiotic or antifungal agents). While medication can be safely used in pregnancy, the lowest risk option is to avoid drug exposure if possible. When medication is to be taken, the risks and benefits must be discussed, particularly for medications with harmful potential, such as addiction. (See "Initial prenatal assessment and first trimester prenatal care", section on 'Medications commonly used in pregnancy'.)
Use of venlafaxine during early pregnancy and risk of birth defects (June 2015)
Venlafaxine is often used as an alternative to selective serotonin reuptake inhibitors for treating antenatal depression, but the risk of birth defects with venlafaxine is not clear due to inconsistent findings across small observational studies. A study of national registries from multiple countries identified infants who were exposed to venlafaxine during the first trimester (n>2700) and infants who were not exposed (n>2,100,000); the analyses controlled for several potential confounding factors, such as maternal age, smoking, diabetes, and use of other medications (eg, antiepileptics) . The risk of major birth defects was comparable for the two groups, as was the specific risk for cardiac defects. However, this study did not address other perinatal risks, such as preterm birth or hypertension, which have been associated with venlafaxine in other studies. (See "Risks of antidepressants during pregnancy: Drugs other than selective serotonin reuptake inhibitors", section on 'Teratogenicity'.)
Expectant management of mild preeclampsia near term (June 2015)
The optimum time for delivery of women with preeclampsia without features of severe disease and stable maternal and fetal conditions at 34 to 36 weeks of gestation is uncertain. The recent randomized HYPITAT-II trial confirmed findings from observational studies showing that most patients with late-onset mild preeclampsia managed expectantly will reach term without progressing to severe disease or developing an adverse outcome . Newborns benefited from the extra time in utero: the rate of respiratory distress syndrome was 70 percent less with expectant management compared with immediate delivery. Mild preeclampsia with onset at 34 to 36 weeks can be managed expectantly to enable further fetal growth and maturation. Delivery is indicated at 37 weeks. (See "Preeclampsia: Management and prognosis", section on 'Preeclampsia without features of severe disease'.)
Gestational age apps (June 2015)
Electronic techniques, such as apps available for download to smart phones, are generally more accurate for determining gestational age than mechanical wheels. However, a high proportion of gestational age apps are also inaccurate . Clinicians and patients should be aware of this possibility when using a gestational age app, and clinicians should test the accuracy of the app they use. UpToDate provides calculators that determine the estimated date of delivery and current gestational age. (See "Prenatal assessment of gestational age and estimated date of delivery", section on 'Calculator'.)
Nicotine replacement therapy during pregnancy (May 2015)
Cigarette smoking during pregnancy is associated with adverse pregnancy outcomes. Nicotine replacement therapy has had limited use in pregnant women because of concerns regarding potential adverse fetal effects and limited evidence supporting efficacy. In a retrospective study of nearly 200,000 children born in the United Kingdom, the rates of major congenital anomalies were not statistically different among infants of women using nicotine replacement therapy, women who smoked, and women who did not use either . System-specific analysis reported an increased risk of respiratory anomalies in the nicotine replacement-exposed children, but the absolute risk was 3 per 1000 births, and based on 10 exposed cases out of 157 children with respiratory anomalies. Given the known benefits of smoking cessation during pregnancy, nicotine replacement therapy appears to be a reasonable treatment option for pregnant women who wish to stop smoking. (See "Cigarette smoking and pregnancy", section on 'Nicotine replacement'.)
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 . 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 . 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 [89-96]. 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'.)
PEDIATRICS: GENERAL PEDIATRICS
Prevention of alcohol use in children and adolescents (October 2015)
Alcohol is frequently used by children and adolescents in the United States and its use is associated with death and serious injury. In August 2015, the American Academy of Pediatrics (AAP) released a clinical report encouraging pediatric clinicians to talk about the dangers of alcohol with children as young as nine years of age, when they may begin to form positive attitudes towards alcohol . The AAP also recommends screening all youth for alcohol use with a structured screening instrument, either as part of more general substance use screening or, if time is limited, with an instrument that focuses on alcohol, such as the two-question screen developed in collaboration with the National Institute on Alcohol Abuse and Alcoholism (table 4). We agree with these recommendations. (See "Screening tests in children and adolescents", section on 'Alcohol and substance use'.)
Ease of use of different epinephrine autoinjectors for anaphylaxis (July 2015)
Epinephrine autoinjectors can be life saving for patients with serious allergies, but even with specific training, many people have trouble using the various devices properly. A randomized trial of mothers of food-allergic children, tested in simulated anaphylaxis scenarios, suggested that the Auvi-Q device, a rectangular cassette that has audible instructions to guide the user through the injection process, was easier to use than non-audible pen devices . When prescribing an epinephrine autoinjector, ease of use, cost, the need for multiple injectors, and patient facility with self-injection should all be considered. (See "Prescribing epinephrine for anaphylaxis self-treatment", section on 'Ease of use'.)
Outcomes of infants with inconclusive newborn screening for cystic fibrosis (July 2015)
CFTR-related metabolic syndrome (CRMS) describes infants with an equivocal diagnosis following newborn screening for cystic fibrosis (CF). These infants usually have elevated levels of immunoreactive trypsinogen, but inconclusive results of subsequent sweat and DNA testing. The natural history of infants with CRMS is unclear. Now, a small study of infants with an initial diagnosis of CRMS reports that 48 percent were later diagnosed with CF, most within the first year of life . Affected individuals had a somewhat milder CF phenotype compared with infants who were diagnosed with CF by newborn screening. These findings highlight the importance of longitudinal clinical and laboratory follow-up of infants with CRMS. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related metabolic syndrome'.)
Updated recommendations for pediatric head lice (May 2015)
Pediculosis capitis is a common condition that can lead to physical discomfort and social stigmatization. An update to the 2010 clinical report on head lice published by the American Academy of Pediatrics incorporates new therapies (spinosad and topical ivermectin), clarifies diagnosis and treatment protocols, and provides guidance for the management of children with pediculosis capitis in the school setting . Examples of major points in the update include recommendations that no child should be excluded from school because of head lice or nits and that pyrethroids remain reasonable first-line therapies for primary treatment of pediculosis capitis in communities where resistance to pyrethroids is unproven. (See "Pediculosis capitis", section on 'Pediculicide selection'.)
Diagnostic accuracy of serial ultrasounds for pediatric appendicitis (April 2015)
In pediatric patients whose initial ultrasound is equivocal for the diagnosis of appendicitis and who have persistent findings, repeat physical examination and a second ultrasound has good diagnostic accuracy and can markedly reduce the use of computed tomography (CT). A prospective observational study of 294 children undergoing acute evaluation for abdominal pain (38 percent with appendicitis) evaluated a protocol stratifying children into three paths: serial physical examination, surgical consultation, and repeat ultrasound if the initial ultrasound was equivocal; discharge home if the initial ultrasound showed a normal appendix; and surgical consultation if the initial ultrasound was positive for appendicitis . This strategy, consistent with our approach, achieved a sensitivity of 97 percent and a specificity of 91 percent; CT was performed in four patients. (See "Acute appendicitis in children: Diagnostic imaging", section on 'Imaging approach'.)
PEDIATRICS: DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS
Genetic testing in autism spectrum disorder (September 2015)
Genetic testing is often performed in children with autism spectrum disorder (ASD) to provide information about prognosis and recurrence. The suggested evaluation has evolved with advances in molecular diagnostic techniques. In a population-based study, the yield of genetic diagnosis with whole-exome sequencing was similar to that with chromosomal microarray (CMA): 8.4 and 9.3 percent, respectively; and 15.8 percent when both tests were performed . Genetic diagnosis was achieved more often in children with higher levels of dysmorphology, suggesting that severity of dysmorphology is predictive of genetic abnormalities . Pending additional studies, we continue to suggest genetic testing by CMA and DNA analysis for fragile X syndrome for all children with ASD, whether or not they have dysmorphic features. (See "Autism spectrum disorder: Diagnosis", section on 'Genetic testing'.)
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 . 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'.)
Effectiveness of pertussis vaccine in infants (May 2015)
Infants younger than 12 months have the highest incidence of pertussis and pertussis-related complications, including death. In a large case control study, having received ≥1 dose of pertussis vaccine was associated with a 72 percent reduction in the risk of death and a 31 percent reduction in the risk of hospitalization in infants ≥6 weeks of age (the minimum age for the first dose of pertussis vaccine) . However, 64 percent of the deaths occurred in infants younger than six weeks. These findings highlight the importance of timely pertussis immunization for infants, as well as maternal immunization during pregnancy and immunization of the infant's close contacts, as recommended by the Global Pertussis Initiative . (See "Diphtheria, tetanus, and pertussis immunization in infants and children 0 through 6 years of age", section on 'Efficacy and effectiveness' and "Immunizations during pregnancy", section on 'Tetanus, diphtheria, and pertussis vaccination' and "Bordetella pertussis infection in adolescents and adults: Treatment and prevention", section on 'Tdap booster'.)
Acetaminophen alone not effective in reducing neonatal pain (August 2015)
Acetaminophen (paracetamol) has been used in the management of mild to moderate procedural and postoperative neonatal pain. However, a recent systematic review of randomized trials found that acetaminophen alone was not more effective than placebo in preventing or reducing pain associated with heel lance or eye examination in newborns . As a result, we do not recommend using acetaminophen as the sole agent in newborns to reduce pain from painful procedures. (See "Prevention and treatment of neonatal pain", section on 'Lack of efficacy'.)
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