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.
GENERAL INTERNAL MEDICINE
Prevention
Aspirin and cancer 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 of treatment (odds ratio 0.76, 95% CI 0.63-0.93) and appeared to be equally effective in women and men [1]. In this same study, aspirin reduced cancer deaths after five years of treatment (odds ratio 0.63, 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 on cancer incidence and mortality 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'.)
Human papilloma virus vaccine for prevention of anal intraepithelial neoplasia — 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 [2]. 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 [3]. 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'.)
Hepatitis B vaccination — 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 [4]. 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'.)
Breast cancer risk and alcohol consumption — 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 [5]. 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'.)
Probiotics for prevention of the common cold — 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 [6]. 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'.)
Screening
Overdiagnosis and breast cancer screening — Overdiagnosis refers to disease that is detected by screening that would not have caused morbidity or mortality if it had not been found. Multiple studies in breast cancer screening suggest that overdiagnosis is a concern, but a precise estimate of the number of screen-detected cancers that represent overdiagnosis is uncertain. A study from Norway, based upon the staggered introduction of screening, reviewed data related to breast cancer detected by screening and compared this with concurrent breast cancer incidence in geographic areas where screening was not available and with historical data for the areas with and without screening to correct for time trends in breast cancer incidence [7]. The study included 39,888 patients with invasive breast cancer, with 7793 diagnosed after screening was introduced. The study estimated the rate of overdiagnosis to be between 15 and 25 percent. (See "Screening for breast cancer", section on 'Overdiagnosis'.)
Revised guidelines for cervical cancer screening — New guidelines for screening for cervical cancer have been issued by the U.S. Preventive Services Task Force (USPSTF) [8] 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) [9]. 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 [10]. 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'.)
Repeat screening for bone mineral density — 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:
In women 65 years of age and older with normal or slightly low bone mass (T score -1.01 to -1.49) at baseline and no risk factors for accelerated bone loss, we suggest follow-up dual-energy x-ray absorptiometry (DXA) in 10 to 15 years. (See "Screening for osteoporosis", section on 'Repeat BMD measurements'.)
Guidelines for screening for colorectal cancer — The American College of Physicians issued a 2012 statement reflecting their review of existing guidelines from other organizations [13]. 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'.)
Prostate cancer screening — 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 [14]. An additional two years of follow-up from ERSPC continues to show similar results to the initial report [15]. 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'.)
Screening for melanoma — 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 [16]. 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'.)
Mortality benefit for screening colonoscopy — 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) [17]. 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'.)
Ultrasound for ovarian cancer screening — A large prospective study with follow-up to 20 years evaluated annual transvaginal ultrasonography for the detection of ovarian cancer in over 37,000 asymptomatic women (aged 50 and older or aged 25 and older with a documented family history of ovarian cancer) [18]. The specificity and positive predictive value for primary invasive epithelial ovarian cancer were 98.5 and 8.9 percent respectively; 11.1 operations were performed per primary ovarian cancer detected. Seventy percent of the 47 screen-detected invasive cancers were stage I or II. The five-year survival rate for women with screen-detected invasive ovarian cancer was higher than for ovarian cancers in unscreened women at the same institution; whether this difference reflects a true mortality difference or biases related to nonrandomized studies (lead time, length time, and healthy volunteer effects) cannot be determined. Additionally, these results reflect findings from a center with high expertise in ultrasound and are not likely to be reproducible in the general community. UpToDate does not recommend screening average-risk women for ovarian cancer. (See "Screening for ovarian cancer", section on 'Pelvic ultrasonography'.)
Lung cancer screening guidelines — The National Comprehensive Cancer Network (NCCN) issued guidelines for lung cancer screening in October 2011 [19]. 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'.)
CT colonography for colorectal cancer screening — 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) [20]. 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'.)
Geriatrics
Sodium phosphate enemas — Sodium phosphate enemas are used in the treatment of constipation and for preparation for flexible sigmoidoscopy. A retrospective series found that sodium phosphate enema use in older adults (mean age 80 years, range 61 to 89 years) was associated with complications, including hypotension and volume depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe hypocalcemia, renal failure, and EKG changes (prolonged QT interval) [21]. In patients over the age of 70 years, we suggest that warm water enemas rather than sodium phosphate enemas be used for the treatment of constipation. Additionally, in deciding on a preparation for flexible sigmoidoscopy in patients over the age of 70 years, the relative risks of oral preparations (eg, polyethylene glycol lavage or magnesium citrate) and sodium phosphate enemas need to be weighed for each individual patient. (See "Management of chronic constipation in adults", section on 'Disimpaction' and "Constipation in the older adult", section on 'Stool softeners, suppositories, and enemas'.)
Anticoagulation for patients with hip fracture — 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'.)
Revised Beers criteria — 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'.)
Inpatient geriatric assessment — 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 — 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
Fibrates and renal function — 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'.)
Monitoring liver function tests — 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'.)
Lovastatin drug interactions — 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'.)
Statins and risk of infection — Some observational studies had suggested that prior treatment with statins might reduce the risk of serious infections or improve outcomes in patients with serious infections. A meta-analysis of 11 randomized trials of statins (n = 30,947) found no effect of statin therapy on infections (relative risk [RR] 1.00, 95% CI 0.96-1.05) or infection related mortality (RR 0.97, CI 0.83-1.13) [29]. Given these results, it is unlikely that prior statin therapy has an important effect on the risk or outcomes of infections. (See "Statins: Possible noncardiovascular benefits", section on 'Sepsis and infections'.)
Intensive statin 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 [30]. (See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents", section on 'SATURN trial'.)
Niacin therapy — 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 [31]. 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 [32]. 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)'.)
Ophthalmology
Embryonic stem cells for retinal disease — In the first report of the safety and tolerability of human embryonic stem (ES) cell use, two patients with advanced retinal disease (dry age-related macular degeneration and Stargardt’s macular dystrophy) received subretinal injections of retinal pigment epithelium (RPE) cells differentiated from human ES cells [33]. At four-month follow-up, RPE proliferation was confined to the subretinal space, and slight improvement in visual acuity was noted in both patients. This preliminary report of human ES cell transplantation demonstrates short-term safety and tolerability of this treatment in humans. Additional studies assessing the dosage, efficacy, and longer-term safety are required prior to widespread clinical application of human ES cell transplantation. (See "Overview of stem cells", section on 'Clinical use of human ES cells'.)
Orthopedics and spinal disease
Spinal manipulation for neck pain — 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 [34]. 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 for low back pain — 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 [35]. 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
Citalopram dose and adverse cardiac effects — The US Food and Drug Administration (FDA) issued new warnings about the dose-dependent effect of citalopram on QT interval prolongation [36]. In August 2011, the FDA warned that doses of citalopram for all patients should not exceed 40 mg [37]. 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'.)
Cognitive-behavioral therapy for chronic pain — 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 [38]. (See "Overview of the treatment of chronic pain", section on 'Cognitive-behavioral therapy'.)
Urology
Anticholinergic medication for overactive bladder symptoms — 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 [39]. Tolterodine was better tolerated than oxybutynin 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
A rare complication of nasal irrigation — 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 [40]. 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 [41]. 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
Same-day discharge after elective percutaneous coronary intervention — 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 [42]. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Early discharge in low risk patients'.)
PRIMARY CARE ENDOCRINOLOGY
Microvascular complications type 1 diabetes — In the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study to the Diabetes Control and Complications Trial (DCCT), intensive insulin therapy 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 [43]. 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'.)
Vitamin D and fractures — 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 [44]. 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 [44]. 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'.)
Exercise and bone mineral density — 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 [45]. 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'.)
Progestins associated with an increased risk of thrombosis — 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 [46]. 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'.)
Intermittent hormonal contraception — No hormonal contraceptive method is approved in the United States 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 [47]. 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 3). (See "Overview of contraception", section on 'Intermittent hormonal contraception'.)
New testosterone preparations — 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) [48-50] and a topical testosterone solution that is applied to the underarm [51]. (See "Testosterone treatment of male hypogonadism", section on 'Testosterone gels'.)
Maintenance of weight loss — 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 [52]. (See "Dietary therapy for obesity", section on 'Maintenance of weight loss'.)
PRIMARY CARE GASTROENTEROLOGY
Risk of esophageal cancer with Barrett's esophagus — 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 [53]. 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 [54]. 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
Safety of dabigatran — 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 [56], 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
Treatment of acute bacterial rhinosinusitis — Guidelines for the treatment of acute bacterial rhinosinusitis (ABRS) have been released from the Infectious Disease Society of American (IDSA) [57]. 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'.)
When to initiate HIV treatment — 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 [58]. 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 various 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".)
Fluoroquinolones and retinal detachment — A nested case-control study of patients who had visited an ophthalmologist found an increased rate of retinal detachment in patients who were currently receiving an oral fluoroquinolone [59]. Past fluoroquinolone use (even if recent) was not associated with retinal detachment, suggesting that retinal detachment may be an acute adverse effect. A possible reason for the increased risk of retinal detachment in patients taking a fluoroquinolone is the destructive effect of this class of agents on collagen and connective tissue. Additional studies are required to confirm this adverse effect. (See "Fluoroquinolones", section on 'Retinal detachment'.)
C. difficile and proton pump inhibitors — 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 [60]. 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'.)
Antibiotics for acute rhinosinusitis — A randomized trial of adult patients (n = 166) presenting to primary care offices who met clinical criteria for acute bacterial rhinosinusitis evaluated whether a 10-day course of amoxicillin, compared to placebo, improved disease-related quality of life as measured by a symptom score [61]. There was no difference between groups at day 3, the primary specified outcome, or at day 10, although there was greater symptom improvement reported by the amoxicillin group at day 7. All patients were also offered symptomatic treatment for relief of pain, fever, cough, and nasal congestion. Since many patients with acute bacterial rhinosinusitis resolve spontaneously within the first 10 days, in the absence of high fever or symptoms suggesting complicated illness, we suggest only supportive care management (mild analgesics, decongestants, and fluid) for patients who present with fewer than 10 days of symptoms. (See "Acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Community-acquired acute bacterial rhinosinusitis'.)
Recurrent C. difficile infection — 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 [62]. (See "Clinical manifestations and diagnosis of Clostridium difficile infection in adults", section on 'Recurrent disease: relapse vs reinfection'.)
Treatment of latent tuberculosis — 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 [63]. 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 [64]. 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 4). (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'.)
Chronic fatigue syndrome — 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 [65] was later partially retracted by the authors [66] and subsequently fully retracted by the editor of the journal in which it was published due to concerns about the validity of the results [67]. Soon after this full retraction occurred, the authors of a similar study [68] retracted their results as well [69]. (See "Clinical features and diagnosis of chronic fatigue syndrome", section on 'XMRV and MLV'.)
PRIMARY CARE NEPHROLOGY
Acetylcysteine and contrast nephropathy — The Acetylcysteine for the prevention of Contrast-induced Nephropathy (ACT) trial showed no benefit over placebo of acetylcysteine (1200 mg orally twice daily) on the incidence of contrast nephropathy among 2308 high-risk patients who were undergoing angiography [70]. The trial was underpowered to exclude a potential benefit of acetylcysteine among patients with severe kidney insufficiency. (See "Prevention of contrast-induced nephropathy", section on 'Acetylcysteine'.)
PRIMARY CARE NEUROLOGY
Meralgia paresthetica — Meralgia paresthetica is a clinical syndrome of pain and dysesthesia in the anterolateral thigh associated with entrapment or compression of the lateral femoral cutaneous nerve. Although the condition is not uncommon, few studies have evaluated the etiology and epidemiology of meralgia paresthetica. However, a recent population-based report found that the most frequent conditions associated with meralgia are obesity, diabetes mellitus, and older age [71]. Compared with the general population, subjects with diabetes have a sevenfold increase in the occurrence of meralgia paresthetica. (See "Meralgia paresthetica (lateral femoral cutaneous nerve entrapment)", section on 'Etiology and epidemiology'.)
PRIMARY CARE ONCOLOGY
Radiation therapy after breast conserving surgery — Radiation therapy (RT) is a standard component of the treatment of women who undergo breast conserving surgery (BCS) for breast cancer. The latest meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group confirmed long-lasting benefits of adjuvant RT after BCS [72]. Compared to BCS alone, the addition of RT after BCS was associated with reductions in the 10-year risk of recurrence and in the 15-year risk of breast cancer death. The benefits were consistently seen in both women with node-positive and node-negative breast cancer at diagnosis. (See "Role of radiation therapy in breast conservation therapy", section on 'Benefits'.)
PRIMARY CARE PULMONOLOGY
Treatment guidelines for acute pulmonary embolism — 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 [73]. (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 for obstructive sleep apnea — 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 [74]. 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
Drugs causing nocturnal leg cramps — 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 [75]. 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'.)
Increased symptomatic OA and knee pain — 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 [76]. 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'.)
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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