The following represent additions to UpToDate since the last version of What’s New that were considered by the authors and editors to be of particular interest.
ADULT MEDICINE
General internal medicine
Screening
New guidelines for screening for cervical cancer have been issued by the U.S. Preventive Services Task Force (USPSTF) [1] and by a combined group representing the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology (ACS/ASCCP/ASCP) [2]. The two sets of guidelines, developed independently, overlap in their major recommendations (table 1). The American College of Obstetricians and Gynecologists (ACOG) is currently reviewing guidelines they last issued in 2009, and ACOG members were involved in the development of the ACS/ASCCP/ASCP guidelines [3]. The two new guidelines advise initiating cervical cancer screening for average-risk women at age 21 and discontinuing screening at age 65 for women who have had adequate negative prior screening. Average-risk women have no history of cervical cancer, DES in utero exposure, or significant immunocompromise (such as HIV infection). Women aged 21 to 29 should be screened every three years with cytology only, and women aged 30 to 65 should be screened by either cytology alone every three years or co-testing (HPV test plus cytology) every five years. The ACS/ASCCP/ASCP prefers the co-testing strategy, while the USPSTF suggests co-testing as an alternative for those women who wish to lengthen their screening interval while accepting an increased risk that colposcopy would be needed. All guidelines advise that cervical cancer screening is not indicated for women who have had a hysterectomy, in the absence of a history of cervical cancer or high-grade cervical cancer precursor. (See "Screening for cervical cancer: Rationale and recommendations", section on 'Recommendations of professional organizations'.)
Data regarding the frequency of follow-up bone mineral density (BMD) testing in women who have had an initial screening test are limited. Two studies provide new related data:
These data suggest that healthy women 65 years of age and older at baseline screening, with normal or slightly low bone mass (T-score -1.01 to -1.49) and with no risk factors for accelerated bone loss, do not require repeat testing for 17 years. (See "Screening for osteoporosis", section on 'Repeat BMD measurements'.)
The American College of Physicians issued a 2012 statement reflecting their review of existing guidelines from other organizations [6]. They recommend individualized assessment of patient risk for CRC in all adults; screening average-risk patients starting at age 50, choosing either a stool-based test, flexible sigmoidoscopy, or colonoscopy; screening patients with high risk starting at age 40 (or 10 years younger than age of affected relative at diagnosis) with colonoscopy; and stopping screening at age 75 years or in adults with a life expectancy less than 10 years. They identify all African Americans as being at high risk. Screening recommendations in UpToDate have not changed and include the option of CT colonography. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'American College of Physicians Guidance Statement'.)
After the 2009 reports of the large European and United States prostate cancer screening trials (ERSPC and PLCO), one of the potential explanations for benefits only being seen in the ERSPC was the shorter duration of follow-up in PLCO. A subsequent publication from PLCO with 92 percent follow-up through 10 years continues to show no mortality benefit with screening [7]. An additional two years of follow-up from ERSPC continues to show similar results to the initial report [8]. There was a 21 percent relative reduction in prostate cancer mortality, but a very small absolute reduction, such that 37 additional cases of prostate cancer would need to be detected by screening to prevent one death from prostate cancer over 11 years. (See "Screening for prostate cancer", section on 'Evidence from randomized trials'.)
A large population-based screening program in the Schleswig-Holstein area of Germany, the SCREEN project, offered screening skin examination for one year (2003 to 2004) to 1.9 million citizens aged ≥20 years; 360,000 individuals participated [9]. Participants were screened either by a nondermatologist trained in skin examination or by a dermatologist directly; nearly 16,000 biopsies were performed and 585 melanomas and lentigo melanomas were identified. The incidence of melanoma increased during the screening period (16 percent higher in men and 38 percent higher in women compared to two years earlier) and returned to preprogram levels when the program was stopped. Ninety percent of the melanomas detected by screening were less than 1 mm thick. Melanoma mortality in 2008 was lower in Schleswig-Holstein than in the rest of Germany and substantially lower than expected based on historical rates for this area. A causal relationship between screening and decreased mortality cannot be definitively concluded from these observational data. Germany initiated a nationwide program to screen adults 35 years and older every two years for the early detection of skin cancer in 2008. We currently suggest periodic full-body skin examination by a trained clinician for individuals at higher risk for melanoma (white men over 50 years, individuals with a history of significant sunburn, or multiple moles). (See "Screening and early detection of melanoma", section on 'Clinician detection'.)
Long-term follow-up of the National Polyp Study (NPS) population found that, at an average follow-up of 16 years, there was a 53 percent reduction in colorectal cancer (CRC) mortality in patients who had adenomas removed compared to the expected CRC mortality rate in the general population (based on data from the SEER program) [10]. CRC mortality in the NPS for the first 10 years following polypectomy was the same for patients found to have adenomatous or nonadenomatous polyps. Although not a randomized trial, this is the first study to strongly indicate a CRC mortality benefit for colonoscopy. The magnitude of the results of this study may not be generalizable to community practice, because NPS colonoscopies were performed by a small number of trained endoscopists and reported rates of CRC following polypectomy were lower for the NPS than reported in other studies. Rates of postpolypectomy surveillance colonoscopies (81 percent in the NPS) may also be higher than is common in the community. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Evidence of effectiveness'.)
The National Comprehensive Cancer Network (NCCN) issued guidelines for lung cancer screening in October 2011 [11]. These guidelines recommend annual low-dose CT scan screening for those at high risk and no routine screening for moderate- or low-risk individuals. High risk was defined as age 55 to 74 years with a 30 pack-year history of smoking and, if no longer smoking, smoking cessation within 15 years; or a 20 pack-year history of smoking with one additional risk factor. The guidelines emphasize that screening should be done within the context of a multidisciplinary program to manage downstream testing. Most other guidelines groups are reviewing current screening recommendations in light of a mortality benefit for high-risk screening demonstrated in the 2011 National Lung Screening Trial, although screening cost-effectiveness is not yet determined. All patients who smoke should be strongly counselled to quit smoking as the most effective intervention to reduce the risk of lung cancer. (See "Screening for lung cancer", section on 'Recommendations for screening by expert groups'.)
A 2011 systematic review of HPV screening, prepared for the US Preventive Services Task Force (USPSTF), concluded that although primary HPV screening for women over age 30 detected more cases of CIN3 or cancer than cytology, evidence to date is too limited to determine the net benefit of HPV testing strategies [12]. The review did not find evidence that the combination of cytology plus HPV testing was more effective than primary HPV screening alone. The authors concluded that primary HPV testing was “very promising” as a screening strategy, but that data from ongoing randomized trials are needed to determine the balance of benefits and harms from an HPV testing strategy, including the potential for overdiagnosis and excess colposcopy. Revised cervical cancer screening guidelines are in draft form [13]. (See "Screening for cervical cancer: Rationale and recommendations", section on 'HPV testing'.)
Another review prepared for the US Preventive Services Task Force, focusing on risk factors for cervical cancer, noted a decline in the incidence of cervical cancer and that evidence supports discontinuing cervical cancer screening in women aged 65 and older who have had adequate screening and are not at high risk [14]. (See "Screening for cervical cancer: Rationale and recommendations", section on 'Stopping age'.)
After the 2009 reports of the large European and United States prostate cancer screening trials (ERSPC and PLCO), one of the potential explanations for benefits only being seen in the ERSPC was the shorter duration of follow-up in PLCO. A subsequent publication from PLCO with 92 percent follow-up through 10 years continues to show no mortality benefit with screening [7]. (See "Screening for prostate cancer", section on 'Evidence from randomized trials'.)
A randomized trial in the Netherlands compared outcomes for two colorectal cancer screening strategies: invitation for colonoscopy or invitation for screening CT colonography (for which patients did not use a cathartic preparation) [15]. The diagnostic yield for advanced neoplasia was greater for individuals who underwent colonoscopy than for CT colonography. However, participation rates were significantly higher for those invited for colonography than for colonoscopy (34 versus 22 percent), so that the diagnostic yield for advanced neoplasia per 100 invitees was essentially the same for both strategies. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Computed tomographic colonography'.)
Prevention
In a meta-analysis of six trials of low-dose aspirin for primary prevention (35,535 participants), aspirin reduced the incidence of cancer after three years treatment (odds ratio 0.76, 95% CI 0.63-0.93) and appeared to be equally effective in women and men [16]. In this same study, aspirin reduced cancer deaths after five years of treatment (odds ratio 0.63, 95% CI 0.47-0.86). The number of cancers in the six trials was too small to determine effects on specific cancers, other than colorectal cancer. While the effect of aspirin increased with trial duration, adverse effects (vascular events and extracranial bleeding) decreased over time. Overall, aspirin reduced the risk of the composite outcome (cancer, major vascular event, or fatal extracranial bleed). (See "Cancer prevention", section on 'Aspirin and other anti-inflammatory drugs'.)
A quadrivalent vaccine has been shown to be effective in preventing infection with human papilloma virus vaccine (HPV) types 6, 11, 16, and 18 and to prevent the development of external genital lesions [17]. A planned substudy of that trial analyzed the impact of the vaccine on the development of anal intraepithelial neoplasia in 602 men who have sex with men [18]. Study subjects were aged 16 to 26 years, had no history or evidence of anal lesions, had five or fewer lifetime sexual partners, and were HIV negative. Administration of the HPV vaccine was associated with a significant decrease in the incidence of anal intraepithelial neoplasia. (See "Anal intraepithelial neoplasia: Diagnosis, screening, prevention, and treatment", section on 'Prevention'.)
In the United States, the Advisory Committee on Immunization Practices recommends that hepatitis B virus (HBV) vaccination be given to unvaccinated adults with diabetes mellitus who are ages 19 to 59 [19]. For older patients with diabetes, vaccination can be administered at the discretion of the treating clinician based on the risk of acquiring HBV and the likelihood of an adequate immune response to vaccination. (See "Hepatitis B virus vaccination", section on 'Other high-risk groups'.)
In the largest cohort study examining the relationship between alcohol and breast cancer, over 100,000 women in the Nurses’ Health Study were followed from 1980 until 2008 [20]. The power of this study enabled detection of a small increased risk of breast cancer for women who had alcohol consumption as low as three to six drinks per week, compared to abstainers. There was a 10 percent increase in risk associated with each 10 g per day of alcohol intake and breast cancer risk was linearly correlated with cumulative lifetime alcohol intake. (See "Overview of the risks and benefits of alcohol consumption", section on 'Breast cancer'.)
A meta-analysis of 10 randomized trials compared probiotics (strains of lactobacilli, bifidobacterium, and propionibacterium) with placebo for the prevention of upper respiratory tract infections [21]. Probiotics decreased the rate of acute respiratory infections, but they had no significant effect on the duration of symptoms. Several flaws were noted in the studies reviewed, related to blinding and concealment, failure to differentiate between bacterial and viral etiologies, and inclusion of few older adults. Higher-quality trials that include older adults are needed before it can be determined whether probiotics have a role in the prevention of respiratory tract infections in adults. (See "The common cold in adults: Treatment and prevention", section on 'Probiotics'.)
Geriatrics
The American College of Chest Physicians (ACCP) has released updated guidelines for the prevention of venous thromboembolic disease in patients undergoing hip fracture surgery [22]. Patients who are not at excess risk of bleeding should be treated prophylactically with one of the following: low molecular weight heparin (LMWH), fondaparinux low-dose unfractionated heparin, a vitamin K antagonist, or aspirin. Preference is given to use of LMWH. All patients should also be treated with intermittent pneumatic leg compression until they are able to ambulate on a routine basis. The guidelines recommend that anticoagulation should be initiated either 12 hours or more preoperatively or 12 hours or more postoperatively and that prophylaxis be extended up to 35 days postoperatively. (See "Medical consultation for patients with hip fracture", section on 'Thromboembolic prophylaxis'.)
The Beers criteria, a list of medications categorized as inappropriate or requiring caution with use for older adults, are the most widely-cited criteria used to assess inappropriate geriatric drug prescribing. The criteria, initially developed in 1991 by an expert consensus panel and last revised in 2003, have been newly updated in 2012 [23]. The 2012 revised Beers criteria are available through the American Geriatrics Society website. The criteria include 53 medications designated in one of three categories: those that should always be avoided; those that are potentially inappropriate in older adults with particular health conditions or syndromes; and those that should be used with caution. New additions to the 34 potentially-inappropriate medications include sliding scale insulin, glyburide, and megestrol. Thiazolidinediones should be avoided in patients with heart failure, and selective serotonin reuptake inhibitors (SSRIs) in patients with falls and fractures. (See "Drug prescribing for older adults", section on 'Beers criteria'.)
A meta-analysis of 22 randomized trials of inpatient comprehensive geriatric assessment by mobile teams or in designated wards found that patients who received comprehensive geriatric assessment were more likely to be alive and in their own homes at 12-month follow-up and less likely to be living in residential care, compared with usual care [24]. There was also a reduction in the combined outcome of death or functional decline. Designated wards appeared to be more effective than mobile units. (See "Comprehensive geriatric assessment", section on 'Acute geriatric care units'.)
Adverse drug events (ADEs) resulting in emergency hospitalizations among older Americans were studied using a nationally-representative electronic database [25]. Four types of commonly-used medication (warfarin, insulin, oral antiplatelet agents, and oral hypoglycemics) accounted for 67.0 percent of the ADEs, while only 6.6 percent of the hospitalizations were attributed to medications identified as potentially inappropriate (using the 2003 Beers criteria). Prevention of ADEs in older adults should target improvements in prescribing practices related to medications used to manage diabetes and prevent thrombotic events. (See "Drug prescribing for older adults", section on 'Adverse drug events (ADEs)'.)
Lipids
In randomized trials, fibrates have been shown to increase creatinine levels. A population-based study found an association between new fibrate use in older patients and nephrologist consultations and hospital admissions for a rise in creatinine level [26]. However, although the rise in creatinine levels seen with fibrates may prompt clinical concern and interventions, it is uncertain that the changes in creatinine reflect renal injury. In the FIELD trial, the increase in serum creatinine with fenofibrate was reversible on discontinuation, and at the end of the trial fenofibrate treatment appeared to have slowed loss of renal function and reduced proteinuria [27]. (See "Lipid lowering with fibric acid derivatives", section on 'Toxicity and drug interactions'.)
In 2012, the US Food and Drug Administration revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications [28]. We agree that routine monitoring of liver function tests in patients receiving statin therapy is not necessary. (See "Statins: Actions, side effects, and administration", section on 'Hepatic dysfunction'.)
New manufacturer recommendations for lovastatin state that the medication is contraindicated in patients treated with most strong CYP3A4 inhibitors (table 2), and that there are dose limitations or recommendations to avoid lovastatin when used in conjunction with a number of other medications [28]. The metabolism of a number of other statins is affected by CYP3A4 inhibitors and manufacturer information for some other statins also includes restrictions and dose limitations when used with specific other medications. (See "Muscle injury associated with lipid lowering drugs", section on 'Concurrent drug therapy'.)
Among the available choices for intensive statin therapy, the two most potent regimens are atorvastatin 80 mg daily and rosuvastatin 40 mg daily. In the SATURN trial, in 1039 patients with known coronary disease, these two regimens had similar effects on the surrogate primary outcome of percent atheroma volume and also had similar clinical outcomes and rates of adverse events [29]. (See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents", section on 'SATURN trial'.)
The 2009 ARBITER 6-HALTS trial found that in patients with CHD or a CHD risk equivalent who were being treated with a statin, extended-release niacin decreased a composite cardiovascular endpoint compared with ezetimibe [30]. In contrast to ARBITER 6-HALTS, the AIM-HIGH trial, which examined a similar population of patients (established cardiovascular disease, low HDL-C, elevated triglycerides, all patients treated with a statin), found no additional benefit to treatment with extended-release niacin [31]. The study was stopped early for futility and because of a concern about increased numbers of ischemic strokes in patients treated with niacin, which were not significantly different from placebo after final adjudication. However, HDL-C levels in the “placebo” arm (which received 100 to 200 mg of niacin daily) increased more than expected, which may have reduced the ability of the trial to detect a real benefit with niacin therapy. Given these results, it is uncertain whether adding niacin therapy improves outcomes in patients who have achieved a low LDL-C level on statin therapy alone, even when such patients have a low HDL-C level or moderately-elevated triglycerides. (See "Lipid lowering with drugs other than statins and fibrates", section on 'Nicotinic acid (Niacin)'.)
Orthopedics and spinal disease
Few data exist on the effects of spinal manipulation in patients with acute neck pain. One trial randomly assigned patients with acute or subacute neck pain to spinal manipulation, pharmacotherapy, or home exercise [32]. Spinal manipulation led to decreased self-reported neck pain up to 52 weeks of follow-up, compared to medications (non-steroidal anti-inflammatory drugs, acetaminophen, narcotics, and/or muscle relaxants). Home exercise led to similar improvements in pain compared to spinal manipulation. This trial was limited by lack of blinding of participants and providers. Due to limitations of current evidence and the small risk for serious adverse outcomes, including permanent impairment or death, manipulation of the cervical spine is not recommended as first-line treatment for acute neck pain. Spinal manipulation may be appropriate for those not responding to conservative measures. (See "Treatment of neck pain", section on 'Spinal manipulation'.)
Tai chi is a Chinese martial art that involves slow movements, breathing exercises, and meditation. In a randomized trial in 160 adults with nonspecific low back pain, those assigned to a tai chi program reported improved pain and disability after 10 weeks of treatment, compared to usual care [33]. Further trials are needed to determine long-term efficacy of tai chi in the treatment of low back pain. (See "Exercise-based therapy for low back pain", section on 'Mind body exercise'.)
Psychiatry
The US Food and Drug Administration (FDA) issued new warnings about the dose-dependent effect of citalopram on QT interval prolongation [34]. In August 2011, the FDA warned that doses of citalopram for all patients should not exceed 40 mg [35]. The new warning, issued in March 2012, advises that the dose of citalopram be limited to 20 mg in patients at risk for increased serum concentrations of citalopram. Risk factors include hepatic impairment, age >60 years, CYP2C19 variants that slowly metabolize citalopram, and concomitant medications that inhibit CYP2C19. (See "Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): Pharmacology, administration, and side effects", section on 'Cardiac'.)
In a randomized trial of patients with chronic widespread pain, symptom improvement at six months was reported in 8 percent of patients assigned to usual care, 35 percent assigned to cognitive-behavioral therapy (CBT) delivered via telephone, and 37 percent assigned to a combination of telephone CBT and exercise [36].
Urology
A systematic review of 86 randomized trials and meta-analysis of 70 trials in patients with overactive bladder symptoms compared differing doses and formulations of four anticholinergic drugs [37]. Tolterodine was better tolerated than oxybutynin, with similar efficacy, and extended-release formulations of these agents were better tolerated than immediate release. Fesoterodine had better efficacy than extended-release tolterodine but caused more dry mouth leading to drug withdrawal. Solifenacin was more effective and better tolerated than immediate-release tolterodine. Data were not available for other comparisons and data did not allow conclusions about comparative costs, long-term outcomes, or the impact on quality of life. (See "Treatment of urinary incontinence", section on 'Antimuscarinics'.)
Primary care allergy and immunology
Two fatal cases of primary amebic meningoencephalitis were reported in patients in the state of Louisiana, resulting from the use of unclean tap water to irrigate the sinuses [38]. The causative amoeba was Naegleria fowleri, an organism that is usually contracted from swimming in freshwater lakes and rivers, geothermal bodies of water, or inadequately chlorinated pools [39]. Although this infection is rare, patients who perform sinus irrigation should be advised to use distilled, sterilized, or previously boiled water if making their own saline solutions. (See "Pharmacotherapy of allergic rhinitis", section on 'Nasal saline irrigation'.)
Primary care cardiology
Many of the adverse outcomes after percutaneous coronary intervention (PCI) are seen within the first 48 hours, leading to the common practice of overnight observation in hospital following PCI. In an observational study of over 107,000 patients undergoing elective PCI, same-day discharge was not associated with an increased risk of death or hospitalization at 30 days [40]. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Early discharge in low risk patients'.)
Primary care endocrinology
In the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study to the Diabetes Control and Complications Trial (DCCT), intensive insulin therapy in patients with type I diabetes, compared with conventional therapy, for 6.5 years during the DCCT significantly reduced the risk of developing impaired renal function over a median follow-up period of 22 years [41]. This decreased risk occurred despite an absence of a difference in A1C values during the post-DCCT trial period. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Nephropathy'.)
A meta-analysis of five trials comparing vitamin D (400 to 1370 units/day) with placebo in over 14,500 elderly men and women showed that vitamin D supplementation alone did not reduce fracture risk [42]. However, a meta-analysis of 11 trials comparing combined supplementation with calcium (500 to 1200 mg/d) plus vitamin D (300 to 1100 units/day) with placebo showed a reduction in fracture risk [42]. In a subgroup analysis, the risk reduction was larger among institutionalized than community-dwelling older individuals. These findings suggest that supplementation with both calcium and vitamin D is required to reduce the risk of fracture. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Calcium versus vitamin D'.)
A meta-analysis of 43 randomized trials (4320 participants) of exercise and bone mineral density (BMD) in postmenopausal women showed a small but significant positive effect of exercise on BMD at the lumbar spine and trochanter compared with controls [43]. Various exercise types, including resistance training, jogging, jumping, and walking, were effective. The most effective type of exercise for BMD of the femoral neck was non-weight bearing high-force exercise (eg, progressive resistance strength training), whereas a combined program (mixture of more than one exercise type) was most effective for lumbar spine BMD. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Exercise'.)
Several new testosterone preparations are available for androgen replacement therapy in hypogonadal men, including two higher concentrations of testosterone gel that allow use of a smaller volume of gel (applied to the upper arm) [44-46] and a topical testosterone solution that is applied to the underarm [47]. (See "Testosterone treatment of male hypogonadism", section on 'Testosterone gels'.)
Achieving and maintaining weight loss is made difficult by the reduction in energy expenditure that is induced by weight loss. In addition, weight loss induces changes in peripheral hormone signals that regulate appetite. Gastrointestinal peptides, such as ghrelin and gastric inhibitory polypeptide, increase after diet-induced weight loss. Ghrelin stimulates appetite, and gastric inhibitory peptide promotes energy storage. Other circulating mediators that inhibit intake (eg, leptin, peptide YY, cholecystokinin, pancreatic polypeptide) decrease. In an observational study of 50 patients who lost a mean of 14 kg through dieting, the hormonal adaptations favoring weight gain were still present one year after initial weight loss [48]. (See "Dietary therapy for obesity", section on 'Maintenance of weight loss'.)
Primary care gastroenterology
Estimates of the incidence of esophageal adenocarcinoma in patients with Barrett's esophagus were reported in a 2010 meta-analysis, with an estimated incidence of 6.3 cases per 1000 person-years [49]. However, a much lower rate of 1.2 cases per 1000 person-years was reported in a subsequent large study using the Danish Cancer Registry [50]. This study suggests that the risk of esophageal adenocarcinoma in patients with Barrett's esophagus may be lower than previously suggested. (See "Management of Barrett's esophagus", section on 'Influence of Barrett's esophagus on mortality'.)
Primary care hematology
Increasing concerns have been raised about the safety of the orally-active direct thrombin inhibitor dabigatran:
These observations, as well as reports of deaths among trauma victims receiving dabigatran [52], have called into question the safety of this agent in trauma patients, older patients, and those with renal disease. (See "Anticoagulants other than heparin and warfarin", section on 'Bleeding and thrombotic events'.)
Primary care infectious disease
Guidelines for the treatment of acute bacterial rhinosinusitis (ABRS) have been released from the Infectious Disease Society of American (IDSA) [53]. Although it is difficult to distinguish viral from bacterial acute rhinosinusitis (ARS), three features suggest the diagnosis of ABRS: 1) persistent symptoms or signs of ARS lasting 10 or more days with no clinical improvement; 2) onset with severe symptoms (fever >39°C or 102°F and purulent nasal discharge or facial pain) lasting at least three consecutive days at the beginning of illness; or 3) onset with worsening symptoms following a viral upper respiratory infection that lasted five to six days and was initially improving. Patients who meet criteria for ABRS should be treated with an antibiotic. The guidelines recommend an empiric course of amoxicillin-clavulanate (500 mg/125 mg orally three times daily or 875 mg/125 mg orally twice daily) for five to seven days for most patients; doxycycline is a reasonable alternative. Doxycycline or a respiratory fluoroquinolone may be used in patients with penicillin allergy. Because of high rates of microbial resistance, macrolides (clarithromycin or azithromycin), trimethoprim-sulfamethoxazole, or oral second- or third-generation cephalosporins should not be used for empiric treatment. (See "Acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Community-acquired acute bacterial rhinosinusitis'.)
In 2012, the expert panel of the United States Department of Health and Human Services (DHHS) issued a major change in the previously-issued HIV treatment guidelines; antiretroviral therapy (ART) is now recommended in all HIV-infected patients, regardless of CD4 cell counts [54]. Supportive arguments for this significant shift in treatment recommendations include the availability of more potent agents with less toxicity and recognition that untreated HIV infection has been associated with increased morbidity and mortality related to complications, including cardiovascular, kidney and liver disease and malignancy. Additionally, earlier therapy may lead to a more robust immunologic recovery compared with deferred therapy, and suppressive ART decreases the risk of sexual transmission and thereby provides a potential public health benefit. (See "When to initiate antiretroviral therapy in HIV-infected patients".)
Proton pump inhibitors (PPIs) may be associated with an increased risk of C. difficile-associated diarrhea (CDAD). The US Food and Drug Administration (FDA) issued a drug safety communication in February 2012 following a review of published literature [55]. Most studies reviewed found that the risk of C. difficile infection or disease, including CDAD, ranged from 1.40 to 2.75 times higher among patients with PPI exposure compared with those without PPI exposure. The relationship between the risk of C. difficile infection and PPI dose and duration of use is uncertain. Given the potential risk of CDAD, the FDA has also recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. (See "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults", section on 'Gastric acid suppression' and "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Clostridium difficile and other enteric infections'.)
Recurrent C. difficile infection often represents relapse rather than reinfection, regardless of the interval between episodes. Among 134 paired stool isolates from 102 patients with recurrent C. difficile infections, isolates obtained 2 to 8 weeks apart were identical in 88 percent of cases; isolates obtained 8 weeks to 11 months apart were identical in 65 percent of cases [56]. (See "Clinical manifestations and diagnosis of Clostridium difficile infection in adults", section on 'Recurrent disease: relapse vs reinfection'.)
Rifapentine is a rifamycin derivative with a long half-life and greater potency against M. tuberculosis than rifampin. A three month regimen of weekly isoniazid (INH) and rifapentine (RPT) given as directly-observed therapy has been shown to be noninferior to a nine month self-administered regimen of daily isoniazid in a randomized, open label international trial in predominantly HIV-negative individuals at high risk for progression from latent tuberculosis infection (LTBI) to active infection [57]. Hepatoxicity occurred more frequently in the INH group while hypersensitivity was more frequent in the combination therapy group. The completion rate was higher for the combination therapy, partially attributable to the administration of combination therapy via directly observed therapy (DOT). Higher completion rates with DOT may also explain some of the difference in efficacy of the two regimens. The Centers for Disease Control and Prevention (CDC) recommends either the three month regimen of isoniazid and rifapentine (directly-observed therapy) or the nine month regimen of isoniazid as equal alternatives for treatment of LTBI in otherwise healthy patients aged ≥12 years with risk for TB reactivation [58]. We favor the three month regimen of INH-RPT for treatment of LTBI in adults when directly-observed therapy is feasible, given its noninferiority to INH and the higher treatment completion rate (table 3). (See "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Treatment regimens' and "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Selecting a regimen'.)
A study that reported the detection of DNA from the retrovirus xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome [59] was later partially retracted by the authors [60] and subsequently fully retracted by the editor of the journal in which it was published due to concerns about the validity of the results [61]. Soon after this full retraction occurred, the authors of a similar study [62] retracted their results as well [63]. (See "Clinical features and diagnosis of chronic fatigue syndrome", section on 'XMRV and MLV'.)
Primary care pulmonology
The ninth edition of the American College of Chest Physicians’ Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis has been released. Key changes in the management of acute pulmonary embolism (PE) include stratification of the decision to initiate empiric anticoagulant therapy according to the degree of clinical suspicion, increased acceptance of fondaparinux as primary therapy, and stratification of the duration of anticoagulant therapy on the basis of bleeding risk [64]. (See "Anticoagulation in acute pulmonary embolism" and "Treatment of acute pulmonary embolism" and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis".)
Exercise may modestly improve OSA even in the absence of significant weight loss. This was suggested by a trial that randomly assigned 43 patients with OSA to undergo exercise training (intervention) or a stretching program (control) for 12 weeks [65]. The exercise program consisted of 150 minutes per week of moderate-intensity aerobic exercise performed four days per week. The aerobic exercise was followed by resistance training two days per week. Patients in the exercise training group had a reduction in their apnea hypopnea index (from 32.2 to 24.6 events per hour of sleep) despite no change in body weight. In contrast, patients in the stretching group did not have any improvement in their apnea hypopnea index. (See "Management of obstructive sleep apnea in adults", section on 'Exercise'.)
Primary care rheumatology
An increased risk of nocturnal leg cramps has been attributed to numerous medications in case reports and small series. A recent large observational study provides the strongest evidence for several of these associations [66]. Analysis of a population-derived pharmacy database involving over 24,000 individuals found that patients initiating use of inhaled long-acting beta agonists, potassium-sparing diuretics, and thiazide-like diuretics were more likely to receive a quinine prescription for nocturnal leg cramps during the year after starting a drug from one of these classes, compared with their likelihood during the year preceding such use. Only small increased risks were seen for loop diuretics and statins. (See "Nocturnal leg cramps", section on 'Etiology'.)
The prevalence of symptomatic osteoarthritis (OA) of the knee was evaluated among patients with radiographic OA in a study involving approximately 700 to 1100 patients from the Framingham Osteoarthritis Study cohort at each of three time periods; the rate approximately doubled in women and nearly tripled in men over a period of 20 years, after adjustment for both age and body mass index [67]. Knee pain and obesity also increased over the same interval in this cohort and in national US survey data. However, increased obesity only explained a portion of the change (about 10 to 25 percent), and the prevalence of radiographic knee OA did not increase during this interval. The precise factors responsible for these increases in symptom prevalence and an increased rate of knee joint replacement surgery during this period are uncertain. (See "Risk factors for and possible causes of osteoarthritis", section on 'Knee'.)
OBSTETRICS/GYNECOLOGY
Obstetrics
The use of oral or intravaginal progestin therapy to prevent miscarriage in women with threatened abortion was supported by a meta-analysis of four randomized trials that found that for women with vaginal bleeding at ≤23 weeks of gestation, the rate of spontaneous abortion was significantly lower with progestin treatment compared with placebo or no treatment (14 versus 26 percent) [68]. (See "Spontaneous abortion: Management", section on 'Threatened abortion'.)
In a population-based study from five Nordic countries of more than 1.6 million live births, selective serotonin reuptake (SSRI) use during the second half of pregnancy (after 20 weeks gestation) was associated with a twofold increase in persistent pulmonary hypertension of the newborn (PPHN) [69]. This resulted in a small absolute increase of PPHN (1.2 per 1000 births for the general population to 2.9 per 1000 births for late prenatal exposure to SSRI).
In a 2011 review of their 2006 public health advisory regarding the possibility of an increased risk of PPHN in infants with late prenatal exposure to SSRIs, the US Food and Drug Administration (FDA) concluded that it was not yet possible to establish a link between SSRI use in pregnancy and PPHN and recommended that health care professionals not alter their clinical management of depression during pregnancy based on a concern of PPHN in the offspring [70]. Of note, the FDA report did not include the Nordic study, as it was published after the FDA review. However, the reported absolute increase in the incidence of PPHN is so small that we continue to suggest following the 2011 FDA recommendation of not altering effective SSRI therapy during pregnancy. (See "Infants with antenatal exposure to serotonin reuptake inhibitors", section on 'Persistent pulmonary hypertension'.)
Gynecology
Hormonal suppression following surgical treatment of endometriosis has been found to decrease recurrence rates, but a beneficial effect on pain and pregnancy rates remains unproven. A randomized trial found that postoperative insertion of the levonorgestrel-releasing intrauterine device, compared with expectant management, resulted in decreased dysmenorrhea and pelvic pain at one-year follow-up [71]. (See "Overview of the treatment of endometriosis", section on 'Postoperative medical therapy'.)
Complex atypical endometrial hyperplasia is generally treated with hysterectomy, with the exception of women who desire future pregnancy and thus are treated medically with progestins. The effectiveness of progestin therapy in a variety of formulations (eg, oral, depot injection, intrauterine device) was illustrated by a meta-analysis of observational studies that found a 66 percent complete response rate, with persistent disease in 14 percent and recurrent disease in 23 percent [72]. (See "Management of endometrial hyperplasia", section on 'Progestin therapy'.)
In a study that assessed the risk of cardiovascular events in 835,826 combined hormonal contraceptives users, use of combined contraceptives containing drospirenone, norelgestromin, or etonogestrel was associated with a significantly-increased risk of venous thrombosis compared with use of standard low-estrogen combined hormonal contraceptives [73]. However, when the analysis was restricted to new users, only drospirenone was associated with a significantly-increased risk of thrombosis. (See "Risks and side effects associated with estrogen-progestin contraceptives", section on 'Venous thromboembolic disease'.)
No hormonal contraceptive method is approved for use only at the time of intercourse (ie, intermittent rather than continuous use), but this approach may be effective. In a systematic review of mostly prospective observational studies of precoital and postcoital use of levonorgestrel as a method of contraception in women who had infrequent intercourse, intermittent use of levonorgestrel was safe and moderately effective as a contraceptive [74]. For the most commonly used regimen (0.75 mg of levonorgestrel within one hour after coitus), the pooled Pearl index was 5.1 pregnancies per 100 woman-years. Pearl indices for standard contraceptive methods are shown in the table (table 4). (See "Overview of contraception", section on 'Intermittent hormonal contraception'.)
Whether there is an association between in vitro fertilization (IVF) and subsequent diagnosis of borderline or malignant ovarian tumors is controversial. In a large retrospective cohort study of ovarian cancer risk in women who underwent IVF and subfertile women who did not undergo IVF, the risk of ovarian neoplasia was significantly increased in the IVF group [75]. There was no dose-response relationship between the number of IVF cycles or the number of oocytes harvested and risk of ovarian neoplasia. Because of limitations in design, this study cannot be considered definitive proof of a cause and effect relationship between IVF and ovarian malignancy. (See "In vitro fertilization".)
Hysterectomy is associated with earlier age at menopause. A prospective cohort study found that menopause occurred 1.9 years earlier in women who had a hysterectomy while premenopausal than those who did not [76]. Among women who underwent hysterectomy, the rate of early menopause was significantly higher in those who had both ovaries removed than those who had one ovary conserved. (See "Overview of hysterectomy", section on 'Earlier menopause'.)
PEDIATRICS
General pediatrics
In December of 2011, an expert panel sponsored by the US National Heart, Lung, and Blood Institute published guidelines to promote a lifestyle for children that reduces the risk of cardiovascular disease (CVD), and to identify and manage the child at-risk for premature atherosclerosis [77]. Key elements of these guidelines included:
The G551D mutation, which is present in about 5 percent of individuals with cystic fibrosis (CF), interferes with activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Ivacaftor (VX-770) is the first approved CF therapy that restores the functioning of a mutant CF protein and was specifically developed to overcome the defect in CFTR function caused by the G551D mutation. In a phase 3 trial, subjects with a G551D mutation treated with ivacaftor experienced an improvement in FEV1 compared with subjects treated with placebo [80]. In addition, ivacaftor reduced the frequency of pulmonary exacerbations and pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg. We recommend ivacaftor for all individuals with CF who carry at least one copy of the G551D mutation and are six years of age or older. Ivacaftor is given at a dose of 150 mg by mouth every 12 hours with fat-containing foods. All individuals with CF should undergo genotyping to determine whether they carry the G551D mutation. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'.)
A meta-analysis of four longitudinal studies examined whether weight loss alters the consequences of childhood obesity. The study confirmed that individuals who were overweight or obese during childhood and remained obese as adults have significantly-increased risks for type 2 diabetes, dyslipidemia, and carotid-artery atherosclerosis and hypertension as adults as compared with individuals who were never obese [81]. For the minority of individuals who were obese as children but achieved and maintained a healthy body weight by adulthood, the risk for most of these disorders reverted to that of an individual who was never obese, except that the risk of hypertension persisted. (See "Comorbidities and complications of obesity in children and adolescents", section on 'Cardiovascular'.)
Obesity in a child’s parents is an important predictor of the child’s risk of persistent obesity. If an infant has two obese parents, the infant’s risk of developing obesity is increased sixfold as compared with an infant without obese parents [82]. This observation offers the possibility of early identification of and intervention for at-risk families. (See "Management of childhood obesity in the primary care setting", section on 'Family factors'.)
A well-appearing child between the age of 3 and 36 months who has a fever without a source and who is completely immunized has a low risk of bacteremia but a substantial risk for a urinary tract infection (UTI) depending upon age, gender, and, in boys, circumcision status. Thus, urine testing and culture in such patients is frequently indicated. In contrast, measurement of complete blood count (CBC), obtaining blood cultures, and prescribing antibiotics is typically not warranted. However, in an observational study that reported national estimates of laboratory testing and antibiotic treatment based upon sampling from a national database of emergency department (ED) visits in the United States, ED clinicians did not perform urine testing in 60 percent of girls with high fever, obtained CBC measurements in 21 percent of visits, and prescribed antibiotics in 20 percent of patients in whom no testing was performed [83]. Thus, ED clinicians may not use laboratory testing or antibiotic therapy appropriately when caring for these patients. (See "Fever without a source in children 3 to 36 months of age".)
Developmental and behavioral pediatrics
Analyses of data from four large health plans sponsored by the US Food and Drug Administration (FDA) and the Agency for Healthcare Research, found no difference in the risk of serious cardiovascular events (ie, sudden cardiac death, acute myocardial infarction, or stroke) between patients (either pediatric or adult) receiving pharmacotherapy for attention deficit hyperactivity disorder (ADHD) and individuals not receiving ADHD therapy [84,85]. In an updated safety review based on these results, the FDA recommended clinicians continue to prescribe ADHD pharmacotherapy according to the professional prescribing label and that patients continue to use prescribed therapy for the treatment of ADHD [86]. (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder", section on 'Risk of sudden unexpected deaths'.)
Pediatric immunizations
An investigational vaccine against group B meningococcus, including three recombinant proteins and outer membrane vesicles from the strain that caused an epidemic in New Zealand, was evaluated in a randomized trial of healthy infants [87]. Infants were given three doses of the group B meningococcal vaccine with or without the routine childhood vaccines. After three doses of the group B meningococcal vaccine, 99 percent or more of infants developed substantial titers (serum bactericidal activity titers ≥5) against two of the three reference strains of meningococcus evaluated. Responses to the routine vaccines given concurrently with the group B meningococcal vaccine were non-inferior to the responses to the routine vaccines given alone, except for the responses to pertactin (a correlate of immunity to pertussis) and serotype 6B pneumococcal polysaccharide. These results in infants suggest that this candidate vaccine is promising for use in infants at increased risk of group B meningococcus. (See "Meningococcal vaccines", section on 'Group B meningococcus vaccines'.)
In October 2011, the Centers for Disease Control and Prevention added a history of intussusception as a contraindication to administration of rotavirus vaccine [88]. A history of intussusception previously had been considered only a precaution. (See "Rotavirus vaccines", section on 'RV5 contraindications' and "Rotavirus vaccines", section on 'RV1 contraindications'.)
A single “supplemental” dose of the 13-valent pneumococcal conjugate vaccine (PCV13) is recommended for healthy children aged 14 through 59 months who were fully vaccinated with the 7-valent pneumococcal conjugate vaccine. The importance of the supplemental dose is highlighted by reports of invasive pneumococcal disease caused by one of the six serotypes unique to PCV13 among children who were eligible for, but did not receive, the supplemental dose of PCV13 [89]. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Supplemental dose'.)
Neonatology
The finding of an elevated conjugated or direct bilirubin level in the perinatal period appears to be a sensitive predictor of biliary atresia (BA). A new study found mild elevations of conjugated bilirubin (>0.3 mg/dL) or direct bilirubin (>0.5 mg/dL) at 24 to 48 hours of life in each of 34 infants who were later diagnosed with BA; total bilirubin concentrations were not elevated [90]. Thus, infants with elevated conjugated or direct bilirubin levels in the perinatal period, even if mild, should be followed closely and evaluated for the possibility of BA. The study does not provide information about the specificity of these tests for BA. (See "Biliary atresia", section on 'Laboratory studies'.)
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.
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