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What's new in primary care

What's new in primary care
Jane Givens, MD, MSCE
Literature review current through: Nov 2022. | This topic last updated: Dec 30, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.


Health benefits of strength training in adults (September 2022)

Evidence for the health benefits of strength training continues to grow. In a systematic review and meta-analysis of 16 studies involving over 250,000 participants, strength training was inversely associated with the risk for cardiovascular disease, cancer, diabetes, and all-cause mortality independent of aerobic exercise [1]. The review was limited to prospective studies of individuals ≥18 years without severe health conditions at baseline and a minimum two-year follow-up, and it likely underestimates these associations as not all studies involved robust training methods. These findings support the importance of incorporating strength training into exercise programs for everyone, particularly older adults. (See "Strength training for health in adults: Terminology, principles, benefits, and risks", section on 'Mortality benefit'.)

Potentially modifiable risk factors for cancer (September 2022)

Strategies to reduce cancer incidence include both screening and prevention. In a study of global cancer burden in 2019, 51 percent of worldwide cancer deaths in males and 36 percent of those in females were deemed attributable to behavioral, environmental and occupational, or metabolic risk factors [2]. Smoking was the leading cause for all adults, while other important factors included alcohol use, high body-mass index, and unsafe sexual practices. Counseling and other strategies to decrease these modifiable risk factors are an important part of preventive health. (See "Overview of cancer prevention", section on 'General lifestyle recommendations'.)

Low-dose aspirin for primary cardiovascular disease prevention (June 2022)

Low-dose aspirin may prevent cardiovascular disease (CVD) in some patients but also increases the risk of bleeding. The 2022 United States Preventive Services Task Force (USPSTF) statement concluded that among people 40 to 59 years of age with a ≥10 percent risk of CVD over the next ten years, there is a small potential benefit of low-dose aspirin [3]. The USPSTF did not recommend starting low-dose aspirin in persons over 60 years without heart disease. We believe the decision to prescribe aspirin for primary prevention should be made by the patient and their provider after discussing individual risks and benefits. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Recommendations of others'.)


Pancreatic cancer surveillance in high-risk individuals (August 2022)

While surveillance for pancreatic cancer in high-risk individuals (HRIs) is recommended by expert groups, the long-term benefits have not been clearly established. In an analysis of 1,731 HRIs enrolled in the multicenter Cancer of Pancreas Screening (CAPS) study, 26 invasive cancers were diagnosed over a >20 year period; cases detected during surveillance were more likely to be early stage and associated with longer survival [4]. In a separate cohort study of 347 carriers of a pathogenic variant in CDKN2A who participated in a longitudinal surveillance protocol and were followed for approximately six years, 30 of the 36 pancreatic cancers detected were resectable at diagnosis; 12 were stage I [5]. Five-year survival was 32 percent in the entire cohort but among the six individuals with stage I tumors who underwent resection, five (83 percent) remained alive at three years. These studies demonstrate that early detection of potentially curable pancreatic cancer in HRIs is possible with frequent image-based surveillance, and that the numbers needed to test to detect a single case of pancreatic cancer are reasonable (194 HRIs in the CAPS analysis and 70 in CDKN2A carriers). (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Diagnostic yield, benefits, and harms'.)


Booster doses with the bivalent COVID-19 mRNA vaccines (September 2022, Modified December 2022)

Booster doses of COVID-19 vaccines are a strategy to improve effectiveness in the setting of waning immunity and immune evasion from circulating SARS-CoV-2 variants. The US Food and Drug Administration authorized two bivalent mRNA booster vaccines that target the spike proteins of both the original SARS-CoV-2 strain and the Omicron B.4/B.5 variants (figure 1 and figure 2) [6,7]. The Centers for Disease Control and Prevention (CDC) now recommends that all individuals ≥5 years old who have completed a primary COVID-19 vaccine series (including those who already received booster doses with monovalent vaccines) receive a single booster dose with one of the bivalent vaccines at least two months after the last vaccine dose; bivalent booster recommendations for children younger than five years old depend on the primary series vaccine received (table 1) [8]. Our approach is consistent with CDC recommendations. Although clinical data evaluating bivalent vaccines are limited, their use is supported by indirect evidence from trials and observational studies in which monovalent booster doses improved vaccine efficacy against infection and severe disease and by studies that indicate at least comparable immunogenicity with bivalent versus monovalent formulations. (See "COVID-19: Vaccines", section on 'Role of booster vaccinations'.)

New ACIP recommendations for seasonal influenza vaccination (September 2022)

In August 2022, the Advisory Committee on Immunization Practices (ACIP) issued new recommendations for seasonal influenza vaccination in the United States [9]. The ACIP now recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4) (table 2). In addition, the approved age indication for the cell culture–based inactivated influenza vaccine has been changed from ≥2 years to ≥6 months. We are in agreement with this guidance. (See "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation' and "Seasonal influenza in children: Prevention with vaccines", section on 'Influenza vaccines'.)

Modified vaccinia Ankara vaccine for monkeypox postexposure prophylaxis (August 2022)

During the 2022 monkeypox outbreak, a modified vaccinia Ankara (MVA) vaccine is being used for postexposure prophylaxis after known or likely exposure. In the United States, given limited vaccine supplies, emergency use authorization was granted for intradermal MVA administration in persons ≥18 years; younger individuals should continue to receive the vaccine subcutaneously [10]. Intradermal administration uses a lower dose compared with the standard subcutaneous route, thus maximizing vaccine supply, and clinical trials suggest similar immunogenicity. However, data on the efficacy of postexposure prophylaxis and intradermal administration remain limited; patients who receive the vaccine should continue to monitor for symptoms after an exposure and reduce their risk of new exposures. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Dose-sparing regimen'.)

Novavax COVID-19 vaccine in the United States (July 2022)

In July 2022, the US Food and Drug Administration issued an emergency use authorization for NVX-CoV2373 (Novavax COVID-19 vaccine) for individuals aged 12 years or older, and the Centers for Disease Control and Prevention subsequently recommended it as an option for COVID-19 vaccination [11]. It is an adjuvanted recombinant protein vaccine, similar to other long-available non-COVID-19 vaccines. In trials conducted prior to the emergence of the Delta and Omicron variants, NVX-CoV2373 efficacy in preventing symptomatic COVID-19 was 90 percent in adults; rare cases of myocarditis were reported among vaccine recipients [12,13]. NVX-CoV2373 may be an attractive option for individuals who prefer a COVID-19 vaccine created with a more established vaccine platform. (See "COVID-19: Vaccines", section on 'Available vaccines'.)

No evidence that PEG is the cause of allergic reactions to mRNA COVID-19 vaccines (July 2022)

When initial reports of allergic reactions to SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccines appeared, the excipient polyethylene glycol (PEG) 2000 was implicated as the possible causative agent because higher molecular weight PEGs and related polysorbates have rarely caused anaphylaxis. However, several case series have documented uneventful mRNA vaccinations in a total of over 300 patients who had known or probable PEG allergy and past reactions to PEG-containing medications [14,15]. These findings suggest that PEG 2000 is not the likely cause of apparent anaphylaxis after vaccination with mRNA vaccines. Patients with past allergic reactions to PEG or polysorbate in other medications can safely receive mRNA COVID-19 vaccines without prior PEG skin testing or other special precautions. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Uncertain role of polyethylene glycol'.)


Vitamin D trials do not show benefit for COVID-19 outcomes (October 2022)

There is growing interest in the role of vitamin D as a facilitator of the innate immune response during SARS-CoV-2 infection. However, two recent trials evaluating the effect of vitamin D supplementation on COVID-19 outcomes did not show a benefit:

In a trial from the United Kingdom, in which 6200 adults were randomly assigned to testing of serum 25-hydroxyvitamin D followed by daily low (800 units) or high (3200 units) dose vitamin D supplementation when the concentration was <30 ng/mL (<75 nmol/L) versus no testing/supplementation, there was no difference in the incidence or severity of COVID-19 during six months of follow-up [16].

In a trial from Norway, in which 34,601 adults were randomly assigned to 5 mL of cod liver oil (400 units vitamin D) or placebo daily for six months, there was no difference in the incidence or severity of COVID-19 during six months of follow-up [17].

In patients with COVID-19, vitamin D supplementation may be necessary to meet the recommended intake or to treat deficiency; however, doses exceeding the upper level intake with the intention of improving COVID outcomes are not advised. (See "Vitamin D and extraskeletal health", section on 'COVID-19'.)

Autoimmune disease and risk of cardiovascular disease (September 2022)

Autoimmune diseases are associated with an increased risk of cardiovascular disease (CVD). In a cohort study of over 440,000 persons without CVD who had a new diagnosis of an autoimmune disease and 2.1 million matched controls, 15 percent of those with an autoimmune disease developed CVD in the following 6.2 years compared with 11 percent of controls [18]. The risk of CVD increased with the number of autoimmune diseases present, and the excess risk compared with the general population was greatest for adults under the age of 45. Providers should be aware of the increased CVD risk, and counsel or treat patients accordingly. (See "Overview of possible risk factors for cardiovascular disease", section on 'Autoimmune disease'.)

Gout flare and risk of subsequent cardiovascular event (August 2022)

Gout is known to be associated with cardiovascular disease; however, the temporal association of cardiovascular events after an acute gout flare had not previously been studied. In a case-control study that included over 62,500 patients with gout in a longitudinal primary care database, of whom nearly 10,500 experienced a cardiovascular event (ie, stroke or myocardial infarction), acute gout flare was associated with increased risk of a cardiovascular event in the next 0 to 60 days (adjusted odds ratio [aOR] 1.93) and 61 to 120 days (aOR 1.57) [19]. These findings highlight the importance of managing cardiovascular risk factors among patients with gout. (See "Lifestyle modification and other strategies to reduce the risk of gout flares and progression of gout", section on 'Treatment of comorbidities'.)

Vitamin D supplementation in community-dwelling individuals did not show a fracture benefit (August 2022)

In the VITAL trial, in which 25,871 community-dwelling men and women (mean age 67 years) were randomly assigned to vitamin D (2000 units daily) or placebo, the two groups had similar rates of total fractures (5.9 versus 6 percent), nonvertebral fractures (5.6 versus 5.7 percent), and hip fractures (0.44 versus 0.43 percent) [20]. The participants were not selected on the basis of vitamin D deficiency, low bone mass, or osteoporosis; approximately 10 percent of the total group had a history of a fragility fracture, and approximately 5 percent were taking osteoporosis medications. The mean 25-hydroxyvitamin D level (in a subset of participants) was 30 ng/mL (75 nmol/L). Community-dwelling adults who are getting adequate vitamin D and calcium from dietary intake as well as sun exposure do not need to take additional supplements. Vitamin D supplementation is typically suggested as part of the treatment of osteoporosis, particularly for patients who are receiving osteoporosis medications. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Calcium and/or vitamin D'.)

Network meta-analysis of insomnia medications in adults (July 2022)

A large number of medications spanning multiple classes are available for treatment of insomnia, but few long-term or comparative trials have been performed. This was illustrated by a network meta-analysis, which identified 154 placebo-controlled randomized trials of 30 different medications for insomnia in nearly 45,000 participants, of which only five trials were longer than four weeks, and nearly all comparisons relied on indirect evidence and a small subset of the total number of trials [21]. While the study concluded that eszopiclone, a benzodiazepine receptor agonist (BZRA), and lemborexant, a dual orexin receptor antagonist (DORA), appeared to be the most favorable medications for overall efficacy and tolerability, confidence was limited by known adverse effects of BZRAs and inconclusive long-term safety data for DORAs. In addition, patients with insomnia seen in clinical practice represent a broader population than those enrolled in clinical trials, and treatment decisions must weigh individual risks and benefits of medications along with all other available therapies. (See "Pharmacotherapy for insomnia in adults", section on 'Our approach'.)


Treatment of iron deficiency in patients with heart failure (November 2022)

Patients with heart failure (HF) who are iron deficient should receive iron replacement, but the benefit of this therapy in patients who are not anemic is unclear. In a recent trial in nearly 1900 patients with HF who had an ejection fraction ≤45 percent, hemoglobin ≥9 g/dL, and evidence of iron deficiency (ie, low ferritin or low transferrin saturation), patients assigned to receive intravenous ferric derisomaltose had lower rates of mortality and hospitalization that did not reach statistical significance when compared with placebo [22]. However, in aggregate, trials of iron replacement in similar patients suggest a favorable effect on reducing hospital admissions. Thus, for most patients with HF and iron deficiency (with or without anemia), we suggest iron replacement with intravenous iron. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

Routine display of a risk estimate in patients with heart failure (October 2022)

Routine risk stratification of patients with heart failure (HF) may lead to improved care, but it is unclear whether this strategy alters physician behavior or improves health outcomes. In a recent trial that included over 3100 patients with HF who were randomly assigned to routine display of a one-year mortality estimate to their clinician via the electronic health record or to usual care, the risk of one-year mortality and 30-day hospital readmission was similar between the groups [23]. In addition, clinician behavior, as measured by the use of guideline-directed medical therapy or advanced HF therapies (eg, cardiac transplantation), was also similar between the groups. The use of a risk model in patients with HF is indicated when the information may help to more accurately convey prognosis to the patient but should not be routinely used to guide therapy. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Predictive models'.)

Allopurinol not effective in secondary cardiovascular disease prevention (October 2022)

Some studies have suggested that allopurinol may reduce cardiovascular disease risk in patients with gout. However, in a trial conducted among over 5000 older adults with ischemic heart disease and no history of gout, rates of cardiovascular disease events were essentially equal among those who received allopurinol or usual care over a five-year period [24]. These results do not support the use of allopurinol for secondary prevention of cardiovascular disease. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Therapies with uncertain or no benefit'.)

Revascularization or medical therapy for ischemic cardiomyopathy (October 2022)

In patients with ischemic cardiomyopathy (ICM), it is unclear whether revascularization of coronary artery disease (CAD) is superior to optimal medical therapy alone. In a trial that included 700 patients with multivessel CAD and reduced left ventricular ejection fraction who were randomly assigned to receive percutaneous coronary intervention (PCI) with optimal medical therapy or optimal medical therapy alone, rates of death or rehospitalization were similar between the groups [25]. However, important factors that are commonly used to guide treatment decisions (eg, patient eligibility for coronary artery bypass grafting and correlation between stress testing and clinical findings) were not reported, limiting the trial's broader application to clinical practice. Revascularization is usually indicated for patients with ICM who have signs or symptoms of obstructive CAD, while optimal medical therapy may be appropriate for patients who do not have a clear association between clinical findings and obstructive CAD or who have advanced heart failure. (See "Treatment of ischemic cardiomyopathy", section on 'Choosing CABG, PCI, or no revascularization'.)

Antibiotic prophylaxis against endocarditis before invasive dental procedures (September 2022)

The efficacy of antibiotic prophylaxis for prevention of infective endocarditis (IE) has not been established. A case-crossover analysis and cohort study performed in nearly 8 million individuals identified an association between invasive dental procedures (particularly extractions and oral surgery) and subsequent IE in individuals at high IE risk [26]. Antibiotic prophylaxis was associated with reduced risk of IE after these procedures. These findings support administration of antibiotic prophylaxis to individuals with high IE risk undergoing invasive dental procedures. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures", section on 'Impact of procedures on risk of endocarditis'.)

Improved outcomes and adherence with a polypill in older patients with myocardial infarction (September 2022)

In patients with recent myocardial infarction (MI), a polypill strategy may simplify treatment and improve treatment adherence, but its efficacy in preventing a secondary cardiovascular event is uncertain. In a trial that randomly assigned nearly 2500 older patients with an MI in the prior six months to either a polypill (containing aspirin, ramipril, and atorvastatin) or usual care, those receiving a polypill had a lower rate of a composite of cardiovascular events (death, nonfatal MI, nonfatal ischemic stroke, or urgent revascularization; 9.5 versus 12.7 percent) over a mean of 36 months [27]. Blood pressure, low-density lipoprotein cholesterol levels, and adverse events were similar between the two groups, and medication adherence was higher in the polypill group. While these results are promising, further studies are needed to confirm these findings. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Polypill'.)

Autoimmune disease and risk of cardiovascular disease (September 2022)

Autoimmune diseases are associated with an increased risk of cardiovascular disease (CVD). In a cohort study of over 440,000 persons without CVD who had a new diagnosis of an autoimmune disease and 2.1 million matched controls, 15 percent of those with an autoimmune disease developed CVD in the following 6.2 years compared with 11 percent of controls [18]. The risk of CVD increased with the number of autoimmune diseases present, and the excess risk compared with the general population was greatest for adults under the age of 45. Providers should be aware of the increased CVD risk, and counsel or treat patients accordingly. (See "Overview of possible risk factors for cardiovascular disease", section on 'Autoimmune disease'.)

Anticoagulation for rheumatic mitral stenosis with atrial fibrillation (September 2022)

Limited data have been available to guide anticoagulant choice in patients with rheumatic mitral stenosis and atrial fibrillation. A randomized trial enrolling over 4500 adults with rheumatic heart disease and atrial fibrillation found that the mortality and stroke rates were higher with rivaroxaban than with a vitamin K antagonist (VKA), and major bleeding rates were similar [28]. Based on these findings, for patients with rheumatic mitral stenosis and atrial fibrillation, we now recommend a VKA rather than a direct oral anticoagulant such as rivaroxaban. (See "Rheumatic mitral stenosis: Overview of management", section on 'Choice of anticoagulant'.)

Efficacy of moderate-dose statin plus ezetimibe for secondary prevention of cardiovascular disease (September 2022)

The long-term efficacy of combination therapy with ezetimibe plus a moderate-dose statin for the secondary prevention of cardiovascular disease (CVD) has not been well studied. In the RACING trial, which randomly assigned nearly 3800 patients with CVD to combination therapy with moderate-dose rosuvastatin plus ezetimibe or high-dose rosuvastatin monotherapy, rates of a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at three years were similar between the treatment groups (9.1 versus 9.9 percent, respectively) [29]. Patients receiving combination therapy were more likely to have low-density lipoprotein cholesterol <70 mg/dL, and discontinuation or dose reduction of the study drug was less frequent in the combination versus monotherapy group. In patients with CVD, ezetimibe plus a moderate-dose statin may be an alternative to high-dose statin therapy, particularly in those with an intolerance to high-dose statins. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Combination therapies'.)

Adverse prognosis with tricuspid regurgitation (August 2022)

There has been growing recognition of the prognostic significance of tricuspid regurgitation (TR). In a study from the National Echocardiography Database of Australia of nearly 440,000 adults, 29 percent had at least mild TR [30]. After adjustment for clinical factors, grades of TR from mild to severe were associated with increasing risk of all-cause mortality and cardiovascular mortality; even mild TR was an independent predictor of increased mortality. These findings highlight the importance of follow-up in patients with TR. (See "Management and prognosis of tricuspid regurgitation", section on 'Prognosis'.)

International validation of the Canadian Syncope Risk Score (June 2022)

Multiple risk stratification tools have been developed to avoid expensive unnecessary admissions for syncope, but none are universally accepted. The Canadian Syncope Risk Score (CSRS) has been validated in several sites across Canada and recently validated in an international, multicenter cohort that included over 2200 adults who presented to an emergency department (ED) with syncope [31]. In nearly 1400 patients classified as low-risk by the CSRS, only 1 percent had a serious clinical event or required a procedure at 30 days. A multivariate regression analysis of the nine individual items of the CSRS found that ED clinician gestalt for the classification of syncope (eg, cardiac syncope, vasovagal syncope, or other) had similar accuracy compared with the entire CSRS. This supports our recommendation that risk stratification tools should be used to assist clinical judgment but cannot replace it. (See "Approach to the adult patient with syncope in the emergency department", section on 'Risk stratification'.)

No reduction in heart failure readmission risk with remote monitoring and financial incentives (June 2022)

In patients with heart failure (HF) who were recently discharged from the hospital, insufficient support from the health care system has been linked to a higher risk of readmission, and systems-based interventions designed to reduce the risk of readmission have questionable efficacy. In a recent trial, over 550 patients recently discharged with HF were randomly assigned to usual care or a complex intervention that included remote scales and electronic pill bottles that generated alerts to clinicians, as well as financial incentives for adherence [32]. Despite more than 3700 alerts generated by the complex intervention, rates of readmission or death were similar between the two groups. The role of telemonitoring in reducing hospital readmission for HF remains unclear; optimal therapy with evidence-based medications is the strategy most likely to reduce the risk of readmission. (See "Systems-based strategies to reduce hospitalizations in patients with heart failure" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction".)


Laboratory monitoring for isotretinoin therapy (September 2022)

Reduced monitoring of liver function and lipid tests in healthy patients receiving isotretinoin has been proposed based upon data that suggest low utility of monthly testing. A Delphi consensus study in which acne experts responded to a series of surveys found at least 70 percent consensus for checking alanine aminotransferase (ALT) and triglyceride levels within one month prior to isotretinoin therapy and after reaching the peak isotretinoin dose [33]. There was also consensus that several other laboratory tests were not necessary, such as complete blood count panels, basal metabolic panels, and select liver function and lipid tests. Although these findings align with the trend towards reduced laboratory monitoring for healthy patients taking isotretinoin, no consensus was achieved for some commonly obtained tests, and additional study is necessary to confirm the best approach to monitoring. Additionally, individual patient characteristics may warrant a different approach to laboratory testing. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Evidence'.)


Choice of second diabetes medication in patients with low cardiovascular risk (October 2022)

In a recent comparative effectiveness trial evaluating the choice of a second medication for treatment of type 2 diabetes, 5047 patients (mean A1C 7.5 percent) on metformin monotherapy and with low baseline cardiovascular risk were randomly assigned to treatment with glargine, glimepiride, liraglutide, or sitagliptin. Glycemic and vascular outcomes over a mean follow-up of five years were reported, as follows:

● The proportion of participants with an A1C ≥7 percent was modestly lower with glargine (67.4 percent) or liraglutide (68.2 percent) than with glimepiride (72.4 percent) or sitagliptin (77.4 percent) [34]. The rate of severe hypoglycemia was highest with glimepiride (2.2 percent) and body weight gain of ≥10 percent lowest with liraglutide (6.1 percent).

● In this cohort with low baseline prevalence of cardiovascular or kidney disease, treatment assignment did not affect the rate of prespecified microvascular and cardiovascular secondary outcomes including peripheral neuropathy, moderately or severely increased albuminuria, reduced kidney function (estimated glomerular filtration rate <60 mL/min per 1.73 m2), major adverse cardiovascular events (MACE), hospitalization for heart failure, or all-cause mortality [35]. However, liraglutide treatment conferred benefit relative to the other three treatments for the incidence of any cardiovascular disease (composite of MACE, hospitalization for unstable angina or heart failure, or any arterial revascularization).

These findings support the selection of a glucagon-like peptide 1 (GLP-1) receptor agonist or basal insulin as second-line treatment for type 2 diabetes in patients without established cardiovascular or kidney disease, with preferential choice of a GLP-1 receptor agonist for patients who wish to avoid weight gain. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease'.)

Lifestyle intervention in older adults with type 2 diabetes (September 2022)

Lifestyle modification is important for improving glycemia in type 2 diabetes mellitus, but there have been few randomized trials evaluating glycemic benefits in older adults. In a recent trial, 100 older adults (mean age approximately 72 years) were randomly assigned to an intensive lifestyle intervention (diet and exercise to achieve a 10 percent body weight loss) for six months or a control intervention (monthly educational group sessions) [36]. After one year, intensive lifestyle modification led to greater reductions in A1C (mean difference 0.9 percent) and body weight (mean difference 8.1 kg), but also caused more episodes of mild hypoglycemia than the control intervention. This trial supports our practice of providing older adults with counseling regarding lifestyle modification, provided the risk of hypoglycemia is minimized through close monitoring and empiric reductions in glucose-lowering therapy in selected individuals. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Lifestyle modification'.)

Updated guidance on gastroparesis (August 2022)

Updated guidance on gastroparesis from the American College of Gastroenterology emphasizes glycemic control in patients with diabetes mellitus and dietary management with a small particle diet [37]. Suggested pharmacologic treatment options include prokinetic agents and antiemetics for symptom control. The guideline also advises against the routine use of central neuromodulators but notes limited evidence of improvement in abdominal pain associated with gastroparesis. In addition, it advises against the use of intrapyloric botulinum injection and herbal therapies for treatment of gastroparesis. Our approach is consistent with the guideline. (See "Treatment of gastroparesis", section on 'Dietary modification'.)

Risk factors for persistent hyperthyroidism after radioiodine treatment of Graves' disease (August 2022)

Radioiodine is one of the effective treatment options for Graves' disease. Approximately 10 to 20 percent of patients have persistent hyperthyroidism six months following radioiodine treatment. Accepted risk factors for persistent hyperthyroidism include more severe hyperthyroidism and large goiter. In a meta-analysis of 4822 patients with Graves' disease, treatment failure also correlated with male sex, administration of radioiodine more than six months after diagnosis, prior use of thionamides, and 24-hour radioiodine uptake ≥60 percent, as well as thyroid volume ≥35.8 mL [38]. These findings may help guide choice of therapy for Graves’ disease. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Persistent hyperthyroidism'.)

Tirzepatide for obesity treatment (June 2022)

Treatment of obesity with glucagon-like peptide-1 (GLP-1) agonists is very effective, but treatment with a dual-acting GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist may be more effective. In a randomized controlled trial including over 2500 adults with obesity (but without diabetes), the dual GIP/GLP-1 receptor agonist tirzepatide once weekly was compared with placebo [39]. At 72 weeks, reduction in body weight at all tirzepatide doses (5, 10, and 15 mg administered subcutaneously once weekly) was greater compared with placebo (-16.1, -22.2, and -23.6 kg, respectively, versus -2.4 kg). While tirzepatide is effective for obesity management in patients with and without diabetes, it does not have regulatory approval for the treatment of obesity alone. (See "Obesity in adults: Drug therapy", section on 'Dual-acting GLP-1 and GIP receptor agonists'.)


Gastric protection during anticoagulation (November 2022)

Gastrointestinal (GI) bleeding can complicate anticoagulation, especially in individuals with prior GI bleeding, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and other risk factors. A new meta-analysis evaluating the benefit of proton pump inhibitors (PPIs) across six observational studies and one randomized trial found an association between PPI use and reduced upper GI bleeding (relative risk 0.67, 95% CI 0.61-0.74) [40]. The correlation was strongest in individuals with NSAIDs or aspirin use and/or with a high bleeding risk score. UpToDate contributors suggest a PPI in individuals at high risk of upper GI bleeding who require anticoagulation. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastric protection'.)

Guidelines on pharmacologic management of irritable bowel syndrome with diarrhea (August 2022)

Updated American Gastroenterological Association (AGA) clinical guidance on the pharmacologic management of irritable bowel syndrome with diarrhea (IBS-D) suggests the use of rifaximin as an option for initial treatment of patients with IBS-D and retreatment with rifaximin in those with recurrent symptoms after an initial response [41]. The guideline also cautions against the use of eluxadoline for management of IBS-D in patients without a gallbladder or those who drink >3 alcoholic beverages daily. Although tricyclic antidepressants can be used to treat IBS symptoms, the guideline recommends against use of selective serotonin reuptake inhibitors. Our approach is consistent with this AGA guideline. (See "Treatment of irritable bowel syndrome in adults", section on 'Antidepressants'.)

COVID-19 vaccination in patients with chronic liver disease (August 2022)

In a study comparing the immunogenicity of COVID-19 vaccines in patients with chronic liver disease versus healthy individuals, chronic liver disease was associated with lower rates of development of positive SARS-CoV-2 neutralizing antibodies (77 versus 90 percent) [42]. Antibody positivity rates were similar among patients with noncirrhotic chronic liver disease, compensated cirrhosis, or decompensated cirrhosis. These data suggest that additional vaccine doses may be needed in patients with chronic liver disease, but further studies are required before making a recommendation for a different vaccine schedule in these patients versus the general adult population. (See "COVID-19: Issues related to liver disease in adults", section on 'COVID-19 vaccination'.)


Low risk of systemic complications after cataract surgery (November 2022)

In a retrospective cohort study of Medicare beneficiaries, the group undergoing cataract surgery had a lower incidence of systemic complications within seven days of surgery than those undergoing other types of elective low-risk outpatient procedures (7.7 versus 13 to 52 percent) [43]. An anesthesia provider was present for most cataract procedures, but systemic complications remained low in the six percent that had no anesthesia care (7.4 percent in this group). These data underscore the low risk of systemic complications in patients undergoing cataract surgery, even without anesthesia care. (See "Anesthesia for elective eye surgery", section on 'Systemic complications'.)

COVID-19 vaccine booster in nursing home residents (August 2022)

COVID-19 vaccination reduces the risk of infection and the threat of serious illness or death among nursing home (NH) residents. The benefit of a fourth dose (second booster) of BNT162b2 (Pfizer monovalent COVID-19) vaccine was demonstrated in a cohort study of over 50,000 NH residents in Israel [44]. Compared with those who only had three doses, residents who received a fourth dose had greater protection against infection and significantly greater protection against hospitalization and death during the Omicron surge. Although these findings support the use of a second booster for NH residents in settings where only monovalent boosters are available, in the United States, a single booster dose with a bivalent vaccine (that targets the spike proteins of both the original SARS-CoV-2 strain and the Omicron B.4/B.5 variants) has replaced prior booster recommendations for adults. (See "COVID-19: Management in nursing homes", section on 'Vaccination'.)

Add-on low-dose glucocorticoids in older patients with rheumatoid arthritis (August 2022)

Although short-term use of low-dose glucocorticoids is common in the management of rheumatoid arthritis (RA), evidence is conflicting regarding its efficacy and safety when used on a chronic basis. In a randomized trial of 451 patients with RA aged 65 years and older, the addition of prednisolone 5 mg daily to disease-modifying therapy resulted in lower measures of disease activity (0.37 points lower on a 10-point scale) and joint damage progression (1.7 points lower on a 10-point scale) compared with placebo after two years of follow-up [45]. However, patients in the prednisolone arm experienced more adverse events (60 versus 49 percent), which consisted mostly of nonserious infections. Thus, while some patients may experience modest benefit with add-on low-dose glucocorticoids, the lowest effective dose should be used to minimize harms, if it is not possible to discontinue glucocorticoid therapy. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of chronic use'.)


Ibrexafungerp for recurrent vulvovaginal candidiasis (December 2022)

Treatment of recurrent vulvovaginal candidiasis (RVVC) has mainly consisted of long-term use of azole drugs such as fluconazole. In a phase 3 trial evaluating extended treatment with either ibrexafungerp, a novel triterpenoid antifungal, or placebo after initial fluconazole treatment in patients with RVVC, more patients receiving extended ibrexafungerp remained without evidence of RVVC four weeks from final dose (65 versus 53 percent). Based on this trial, the US Food and Drug Administration recently approved RVVC as a new indication for use of ibrexafungerp [46]. Although the duration of treatment benefit and efficacy against non-Candida species are not yet known, ibrexafungerp offers patients with RVVC another treatment option. (See "Candida vulvovaginitis: Treatment", section on 'Triterpenoid extended treatment'.)

Progestogens and risk of venous thromboembolism (September 2022)

Historically, estrogens but not progestogens were avoided in patients at increased risk of venous thromboembolism (VTE) who desired contraception or experienced abnormal uterine bleeding. In a case-control study that matched >21,000 reproductive-age patients with acute VTE with patients without prior VTE, current use of depot medroxyprogesterone acetate (DMPA), norethindrone acetate, or MPA was associated with an increased risk of VTE compared with non-use; the levonorgestrel-releasing intrauterine device and oral norethindrone were not associated with increased risk [47]. Study limitations included potential bias from patient selection and treatment indication. When counseling any patient about use of DMPA or high dose oral progestogens, we discuss the possibly increased risk of VTE and consider the patient's other potential risk factors for VTE when making treatment decisions. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk'.)

Vaginal estrogen therapy in patients with a history of breast cancer (August 2022)

Low-dose vaginal estrogen is an effective treatment for moderate to severe symptoms of genitourinary syndrome of menopause (GSM) unresponsive to nonhormonal management (vaginal moisturizers, lubricants), but its safety in patients with breast cancer is unclear. In a study of postmenopausal patients with a history of early estrogen-positive breast cancer treated with aromatase inhibitors (AI), those who used vaginal estrogen after the breast cancer diagnosis had a higher risk of breast cancer recurrence compared with nonusers (adjusted hazard ratio 1.39, 95% CI 1.04-1.85) [48]. This association was not seen in patients treated with tamoxifen. While there are several limitations to this study, these data support our general practice of prescribing vaginal estrogen for management of GSM in patients with breast cancer treated with tamoxifen but not those treated with AI. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Patients with breast cancer'.)

Treatment of recurrent vulvovaginal candidiasis (July 2022)

Patients with recurrent vulvovaginal candidiasis (RVVC, defined as ≥3 culture-confirmed episodes in ≤12 months) who do not respond to oral fluconazole therapy have had few other treatment options. In an industry-sponsored trial comparing treatment and maintenance with either oteseconazole (a novel azole) or fluconazole/placebo in 185 females with active RVVC, fewer patients receiving oteseconazole experienced ≥1 culture-confirmed candidiasis episodes during the 48-week maintenance phase compared with fluconazole/placebo (5 versus 42 percent, respectively) [49]. Where available, oteseconazole is a therapeutic option for patients with culture-confirmed RVVC who do not respond to fluconazole therapy and who are not pregnant, attempting pregnancy, or lactating. (See "Candida vulvovaginitis: Treatment".)

Levonorgestrel dose for emergency contraception in individuals with obesity (June 2022)

Because levonorgestrel (LNG) emergency contraception (EC) appears to be less effective in individuals with obesity, doubling the LNG EC dose has been proposed to improve efficacy in this population. However, in a randomized pharmacodynamic trial comparing usual (1.5 mg) versus double-dose (3 mg) LNG EC in 70 individuals with obesity and a dominant follicle ≥15 mm on ultrasound, the proportion of individuals that achieved at least five days with no evidence of rupture was not significantly different between groups, and the time to follicle rupture was also similar for both groups [50]. As there was no clear reduction or delay in ovulation, we use the 1.5 mg LNG EC dose for all individuals but counsel those with obesity that other options (eg, copper intrauterine device) are more effective. (See "Emergency contraception", section on 'Impact of body weight'.)


Acupuncture in aromatase inhibitor-induced joint pain (December 2022)

For patients with breast cancer who experience aromatase inhibitor (AI)-related joint pain, a randomized trial previously demonstrated short-term improvements with acupuncture over sham acupuncture and waitlist control. Now, with longer follow-up, patients assigned to 12 weeks of acupuncture experienced a median improvement of approximately one point on a pain scale of 0 to 10 at 52 weeks compared with the other groups [51]. We consider acupuncture to be a useful adjunctive or alternative option to pharmacologic strategies in patients with breast cancer who experience AI-induced joint pain. (See "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Musculoskeletal pains and stiffness'.)

Risk of second primary cancers in male breast cancer survivors (November 2022)

The risks for second primary cancers among male breast cancer survivors is being evaluated. In one study that included data from over 10,000 male breast cancer survivors, the standardized incidence ratio (SIR) of a second primary cancer, relative to healthy male controls, was 1.3; specifically, there were increased risks of colorectal (SIR 1.3), pancreatic (SIR 1.6), and thyroid (SIR 5.6) cancer [52]. Male breast cancer survivors should engage in cancer screening according to age, family history, and genetic risk factors, if present. (See "Breast cancer in men", section on 'Post-treatment surveillance'.)

IVIG for vaccine-induced immune thrombotic thrombocytopenia (October 2022)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenoviral-vectored COVID-19 vaccines that presents with thrombocytopenia and thrombosis. Emerging evidence on management continues to support a role for intravenous immune globulin (IVIG) as a component of therapy, along with anticoagulation. In a new nonrandomized study involving 99 individuals with VITT presenting with cerebral venous thrombosis, receipt of IVIG was associated with lower mortality (29 versus 70 percent) [53]. In contrast, the choice of anticoagulant (heparin versus a nonheparin agent) and receipt of a platelet transfusion were not associated with statistically different mortality rates. We continue to suggest IVIG plus a nonheparin agent, especially if there is concern for possible heparin-induced thrombocytopenia (HIT; including delayed or spontaneous HIT). (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'IVIG'.)

Possible increased risks of complications in sickle cell trait (August 2022)

Sickle cell trait is considered a benign carrier state with normal life expectancy and rare increased risks of certain complications (renal medullary carcinoma, splenic infarction at high altitude). Previous studies of cardiovascular complications did not show an increased risk (or showed no increased risk). A new study from the United Kingdom Biobank raises the possibility of increased risks of diabetes, hypertension, heart disease, chronic kidney disease, and retinopathy [54]. The study was based on billing codes and lacked the intensity of monitoring in prior studies; thus, the true risks remain unclear. (See "Sickle cell trait", section on 'Inadequate evidence or conflicting results on the risk of hypertension, diabetes, heart disease, or stroke'.)

ASCO guideline on exercise and diet during cancer treatment (July 2022)

Previous guidelines from the American Society of Clinical Oncology (ASCO) for management of adult cancer survivors with fatigue recommended 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with an additional two to three strength training (eg, weight lifting) sessions weekly. A new guideline addressing the benefits of exercise and diet during active cancer treatment concluded that exercise leads to significant improvements in cardiorespiratory fitness, strength, and fatigue, moderate reduction in sleep disturbance, and a low frequency of adverse effects [55]. For patients with lung cancer, preoperative exercise may reduce hospital stay and the risk of postoperative complications. Oncology providers should recommend aerobic and resistance exercise during active, curative-intent cancer treatment and may recommend preoperative exercise for patients undergoing surgery for lung cancer. Neutropenic diets are not recommended to prevent infection in patients with cancer during active treatment. (See "Cancer-related fatigue: Treatment", section on 'Exercise' and "Overview of the initial treatment and prognosis of lung cancer", section on 'NSCLC'.)


Nirmatrelvir-ritonavir in vaccinated individuals with COVID-19 (October 2022)

A large randomized trial previously demonstrated that nirmatrelvir-ritonavir (Paxlovid) substantively reduced hospitalization and death in unvaccinated individuals with COVID-19 and risk factors for severe disease; accumulating observational data suggest that high-risk vaccinated individuals also benefit. In a study of 1130 vaccinated adults who received nirmatrelvir-ritonavir within five days of COVID-19 diagnosis and 1130 controls matched for age, gender, race, and comorbidities, nirmatrelvir-ritonavir was associated with a lower rate of emergency department visits, hospitalization, and death (odds ratio 0.5) [56]. All 10 deaths were among those who had not been treated. In another study, nirmatrelvir-ritonavir was associated with a reduction in hospitalization from 59 to 15 cases per 100,000 person-days among mostly vaccinated patients ≥65 years old [57]. Despite the limitations of observational data, these data highlight the potential clinical impact of nirmatrelvir-ritonavir among vaccinated individuals with Omicron subvariant infection and support our recommendations to treat patients at risk for severe disease, including otherwise healthy individuals ≥65 years old, regardless of vaccination status (algorithm 1). (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Efficacy and rationale'.)

COVID-19 vaccine booster in nursing home residents (August 2022)

COVID-19 vaccination reduces the risk of infection and the threat of serious illness or death among nursing home (NH) residents. The benefit of a fourth dose (second booster) of BNT162b2 (Pfizer monovalent COVID-19) vaccine was demonstrated in a cohort study of over 50,000 NH residents in Israel [44]. Compared with those who only had three doses, residents who received a fourth dose had greater protection against infection and significantly greater protection against hospitalization and death during the Omicron surge. Although these findings support the use of a second booster for NH residents in settings where only monovalent boosters are available, in the United States, a single booster dose with a bivalent vaccine (that targets the spike proteins of both the original SARS-CoV-2 strain and the Omicron B.4/B.5 variants) has replaced prior booster recommendations for adults. (See "COVID-19: Management in nursing homes", section on 'Vaccination'.)

Vaccine-derived poliovirus infection in Rockland County, New York (August 2022)

In June 2022, poliovirus was confirmed in an unvaccinated, immunocompetent adult resident of Rockland County, New York hospitalized with acute flaccid lower limb weakness [58]. Vaccine-derived poliovirus type 2 was detected in the patient's stool and was also identified from wastewater samples in two neighboring New York counties, reflecting community transmission. The patient had not traveled internationally during the presumed exposure period; therefore, these findings suggest transmission within the United States from a person who received a type 2-containing oral polio vaccine abroad. Unvaccinated individuals remain at risk for paralytic poliomyelitis if they are exposed to either wild or vaccine-derived poliovirus; all individuals should stay up to date on recommended poliovirus vaccination. (See "Poliomyelitis and post-polio syndrome", section on 'Epidemiology'.)

Risk of long COVID in Delta versus Omicron variants (June 2022)

Persistent symptoms following acute COVID-19 infection (eg, long COVID) are common. Recent evidence suggests that the prevalence of persistent symptoms may vary depending on the COVID-19 variant. In an observational study including over 97,000 vaccinated individuals in the United Kingdom, subsequent infection with the Omicron variant was associated with a lower risk of developing persistent symptoms compared with Delta (4.5 versus 10.8 percent) [59]. Findings were consistent regardless of the interval between vaccination and infection. However, methodologic issues (eg, self-reporting through an electronic "app" and shorter duration of follow-up for Omicron versus Delta patients) limit the interpretation of these findings, and further research is needed. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)


Finerenone in patients with diabetic kidney disease (November 2022)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors and finerenone (a nonsteroidal mineralocorticoid receptor antagonist) prevent important adverse kidney and cardiovascular outcomes in patients with diabetic kidney disease (DKD). The 2022 guidelines from the American Diabetes Association (ADA) and the Kidney Disease: Improving Global Outcomes (KDIGO) on the treatment of patients with DKD advise the use of SGLT2 inhibitors in all patients with DKD; they also advise the use of finerenone in patients who have increased albuminuria despite treatment with an angiotensin inhibitor and an SGLT2 inhibitor [60,61]. We agree with these guidelines and now suggest use of finerenone in patients with albuminuria despite other recommended therapies, except when serum potassium is elevated (serum potassium >4.8 mEq/L or estimated glomerular filtration rate <25 mL/min/1.73 m2). (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

Individual-level differences between estimated and measured GFR (August 2022)

UpToDate recommends using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to calculate estimated glomerular filtration rate (eGFR) in most clinical settings. In an analysis of more than 3000 participants from four cohorts in the United States, although the median difference between eGFR and measured GFR (mGFR) was only 0.6 mL/min per 1.73 m2, the individual-level differences were often large, and CKD staging based upon eGFR varied from staging based upon mGFR in as many as one-third of individuals [62]. Clinicians should therefore be aware that individual-level differences between eGFR and mGFR can be clinically relevant; in addition, differences between eGFR and mGFR can be large enough to impact CKD staging. (See "Assessment of kidney function", section on 'eGFR from creatinine (primary approach)'.)

Risk of arterial and venous thromboembolism in nephrotic syndrome (July 2022)

Patients with the nephrotic syndrome are at increased risk for venous and arterial thrombosis compared with the general population. In a large Danish registry study that followed nearly 4000 adults with first-time nephrotic syndrome for 10 years, the 10-year absolute risks of arterial and venous thromboembolism were 14 and 8 percent, respectively, compared with 9 and 3 percent, respectively, in age- and sex-matched controls without the nephrotic syndrome [63]. The risks of ischemic stroke and myocardial infarction were higher than those of other types of thromboembolism. These findings support those of prior studies and highlight the long-term risk of thromboembolic disease among patients with the nephrotic syndrome. (See "Hypercoagulability in nephrotic syndrome", section on 'Epidemiology'.)

Remote monitoring of self-measured blood pressure and blood pressure control (July 2022)

Self-measurement of blood pressure (at home) may improve blood pressure control in patients with hypertension, especially if integrated with other supportive interventions. In a meta-analysis of 18 randomized trials, blood pressure self-measurement combined with mobile or web-based telemonitoring led to greater decreases in systolic and diastolic blood pressure compared with usual care,, possibly due to increased patient engagement and adherence [64]. Patients who are interested in self-monitoring should be provided with adequate training in the machine's use, and the device should be checked for accuracy approximately once yearly. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring", section on 'Possible improvement in blood pressure control with SMBP'.)


Risk of progression to dementia in Down syndrome (October 2022)

Down syndrome (DS) is now considered a genetically determined form of Alzheimer disease (AD), with an estimated age of onset (53.8 years) and age of death (58.4 years) similar to that seen in autosomal dominant AD [65]. In one series of 632 adults with DS and varying levels of cognitive disability (436 asymptomatic, 69 with prodromal AD, and 127 with AD dementia) followed for five years, progression to AD dementia was seen in 17.1 percent of asymptomatic patients and was age dependent (0.6 percent for age <40 years, 21.1 percent for 40 to 44 years, 41.4 for 45 to 49 years, and 57.5 for ≥50 years) [66]. Patients with DS should be monitored closely for cognitive decline, particularly after age 40 years. (See "Down syndrome: Management", section on 'Alzheimer disease'.)

Delayed functional improvement after intracerebral hemorrhage (September 2022)

Functional improvement after intracerebral hemorrhage (ICH) can be slow and the temporal trajectory is often uncertain. In an analysis of individual patient data from two clinical trials in nearly 1000 patients with intracerebral or intraventricular hemorrhage, 72 percent of patients had a poor functional outcome at 30 days [67]. By one year, 46 percent had recovered further and achieved a good functional outcome, including 211 (30 percent) who were functionally independent. Acute ICH complications such as sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for a gastrostomy feeding tube were predictors of poor outcome at one year. These results support the practice of providing aggressive acute treatment of patients with ICH and sustained rehabilitation to help avoid premature withdrawal of support and improve long-term outcomes. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Functional recovery'.)

Incidence of isolated sleep paralysis in the general population (September 2022)

Episodes of sleep paralysis, in which individuals awaken during rapid eye movement (REM) sleep and are temporarily unable to move or call out, are a classic feature of narcolepsy but can also occur as an isolated phenomenon. The incidence in otherwise healthy adults has not been well defined, however. In a representative sample of the United States population that included >12,000 adults, 10 percent reported having had one or more episodes of sleep paralysis in the past year [68]. Risk factors included sleep deprivation, younger age, posttraumatic stress disorder, chronic pain, and depression. Patients who report sleep paralysis should be queried for other signs of narcolepsy (eg, excessive daytime sleepiness, cataplexy) but in their absence, reassured about the benign nature of these events. (See "Approach to abnormal movements and behaviors during sleep", section on 'During REM sleep'.)

No benefit of anti-synuclein monoclonal antibodies in patients with Parkinson disease (August 2022)

Anti-synuclein strategies are being investigated as potential disease-modifying therapies for Parkinson disease (PD) and related disorders, but results have been disappointing thus far. In patients with early-stage PD, trials of two different monoclonal antibodies directed at alpha-synuclein, cinpanemab and prasinezumab, each showed similar clinical and radiographic outcomes in the active treatment and placebo groups at 52 weeks [69,70]. The cinpanemab trial also reported no clear differences at 104 weeks in a blinded extension phase, which was halted due to lack of efficacy. Studies of other therapies directed against alpha-synuclein in earlier stages of development are ongoing. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Alpha-synuclein misfolding, aggregation, and toxicity'.)

Combination pharmacotherapy for painful diabetic neuropathy (August 2022)

Combination pharmacotherapy is frequently used for patients with painful diabetic neuropathy that does not respond to initial monotherapy, despite limited data to support the efficacy of this practice. In a multicenter trial of 130 patients with painful diabetic neuropathy who were given initial monotherapy with amitriptyline, pregabalin, or duloxetine, those whose pain did not improve at six weeks were given a second agent from a different pharmacologic class [71]. At 16-week follow-up, combination strategies consisting of pregabalin added to amitriptyline, amitriptyline added to pregabalin, or pregabalin added to duloxetine all provided greater benefit than monotherapy, and each strategy provided similar (approximately 50 percent) pain reduction relative to baseline pain. These results support the strategy of combination pharmacotherapy for patients with painful diabetic neuropathy that does not respond to initial monotherapy. (See "Management of diabetic neuropathy", section on 'Inadequate response to initial therapy'.)

Dosing of dopamine agonists for restless legs syndrome (June 2022)

Dopamine agonists (eg, pramipexole, ropinirole) are an effective treatment for restless legs syndrome (RLS) but require monitoring and precautions to avoid serious side effects such as confusion, excessive daytime sleepiness, and impulse control disorders. Use of higher doses also increases the risk of paradoxical worsening of RLS symptoms (augmentation). In a United States prescription database study that included nearly 400,000 patients with RLS receiving treatment with dopamine agonists, 19 percent of patients were prescribed higher than recommended doses of dopamine agonists for RLS [72]. To reduce the risk of augmentation and other side effects, doses for RLS should not generally exceed the limits in the table (table 3); effective doses for RLS are lower than those used in Parkinson disease. (See "Management of restless legs syndrome and periodic limb movement disorder in adults", section on 'Side effects and monitoring'.)


Undiagnosed concussion and long-term sequelae (November 2022)

Few studies have assessed the long-term risks associated with an undiagnosed sports-related concussion (SRC). In an observational study performed by the Concussion Assessment, Research, and Education (CARE) Consortium involving nearly 30,000 collegiate athletes and military personnel, individuals who described having sustained one or more undiagnosed concussions performed significantly worse on multiple neurocognitive assessments at subsequent baseline evaluations compared with those whose previous concussions were diagnosed [73]. These findings suggest possible long-term harm when SRC is not diagnosed promptly and managed appropriately. (See "Clinic-based evaluation of sports-related concussion in older adolescents and adults", section on 'Intrinsic risk factors'.

Success rates for meniscus repair (October 2022)

Little high-quality evidence is available about surgical repair of a torn meniscus. A newly published meta-analysis of 27 studies (primarily small case series) involving 1630 meniscal repairs reported an overall success rate of 80.5 percent at five years when modern surgical techniques were employed [74]. The study noted that success rates were higher for lateral versus medial meniscus repair (87.4 versus 76.1 percent) and that concomitant anterior cruciate ligament reconstruction did not affect the success of meniscal repair. (See "Meniscal injury of the knee", section on 'Arthroscopic or open surgery'.)

Athletic benefit of caffeine supplementation does not diminish with habitual caffeine intake (October 2022)

Research suggests that caffeine supplementation, when taken in appropriate doses, can improve exercise capacity and power in some athletes. Whether habitual caffeine intake diminishes such effects has not been well studied. In a systematic review and meta-analysis of 60 studies (over 1100 athletes) that reported the effects of habitual and supplemental caffeine intake on performance, researchers found that habitual, dietary consumption of caffeine (eg, daily coffee) does not appear to diminish its ergogenic effects when taken as a supplement to improve athletic performance [75]. Consistent with other studies, the review found no added benefit from high doses (6 mg/kg). (See "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Caffeine'.)

Return to college academics following concussion (July 2022)

In a multisite, prospective study of >1700 college athletes in the United States with a sports-related concussion (SRC), the median time until return to full academics was six days [76]. Based upon adjusted analysis, athletes who resumed full academic work while still symptomatic were 21.5 percent less likely to return to full sport participation by 14 days and 19.1 percent more likely to experience a prolonged recovery lasting >28 days. Gradual resumption of mental and physical work without exacerbation of symptoms, along with close supervision of this process remain guiding principles for the management of older adolescents and adults recovering from an SRC. (See "Clinic-based management of sports-related concussion in older adolescents and adults", section on 'Return to learn and work'.)

Physical fitness and COVID-19-related morbidity (July 2022)

Evidence is growing that physical fitness confers benefit in those infected with COVID-19. In a retrospective, nationwide study performed in South Africa of over 65,000 people participating in a physical activity rewards program, those with high physical activity levels (>150 minutes/week) suffered substantially lower morbidity from complications of COVID-19 infection than those with low physical activity levels (<60 minutes/week) [77]. Patients with high activity levels prior to becoming infected experienced lower rates of hospitalization, intensive care unit admission, mechanical ventilation, and death. These findings emphasize the importance of maintaining exercise programs during the pandemic. (See "COVID-19: Return to sport or strenuous activity following infection", section on 'Impact of physical fitness on clinical course'.)

Protein supplementation for fracture healing (July 2022)

While general guidance for patients recovering from a fracture often includes ensuring that protein intake is adequate, very few controlled trials have assessed the role of protein in fracture healing. In a single-center trial of 400 patients with pelvic or extremity fractures requiring surgical repair, those assigned to receive essential amino acid supplementation had lower overall complication rates (30.5 versus 43.8 percent) and significantly less early skeletal muscle wasting than those assigned to standard care and nutrition [78]. While the trial was not completely blinded and further study is needed, these results support guidance for adequate daily protein intake in patients with healing fractures. (See "General principles of definitive fracture management", section on 'Overview and basic measures including nutrition'.)

Management of Achilles tendon rupture (June 2022)

The relative benefits of surgical versus nonoperative management of Achilles tendon rupture are a subject of ongoing research. In a multicenter trial of 526 patients with acute Achilles tendon rupture who were randomly assigned to nonoperative management, minimally invasive surgical repair, or open surgical repair, functional outcomes were not significantly different at 12 months [79]. However, patients managed nonoperatively had a higher rate of rerupture compared with patients managed surgically (6.2 percent versus 0.6 percent). We refer all patients with Achilles tendon rupture for surgical consultation to discuss operative and nonoperative treatment options. Patients wishing to return to heavy labor or a demanding sport that involves sprinting and jumping often opt for surgical repair. (See "Achilles tendinopathy and tendon rupture", section on 'Surgery versus nonoperative treatment'.)


Position statement on obstructive sleep apnea in the transportation industry (October 2022)

The American Academy of Sleep Medicine (AASM) has published a position statement on recognizing and treating obstructive sleep apnea (OSA) in commercial drivers and other individuals in safety-sensitive transportation occupations [80,81]. The documents outline roles for key stakeholders, including legislators, employers, law enforcement, payers, health care professionals, and vehicle operators. The AASM recommends that commercial drivers be referred to a sleep medicine specialist for clinical sleep evaluation and diagnostic testing in the presence of a body mass index (BMI) ≥40 kg/m2, fatigue or sleepiness while on duty, involvement in a sleepiness-related crash or accident, or a BMI ≥33 kg/m2 plus either type 2 diabetes or hypertension requiring two or more medications. (See "Drowsy driving: Risks, evaluation, and management", section on 'Special considerations in commercial drivers'.)

Risk of acute exacerbation of interstitial lung disease after COVID-19 vaccination or infection (August 2022)

Whether the COVID-19 mRNA vaccine affects idiopathic pulmonary fibrosis (IPF) remains unclear. In a new case series including four patients with IPF, COVID-19 mRNA vaccination was temporally associated with acute exacerbations of the underlying lung disease [82], consistent with previous case reports. However, earlier data and clinical experience suggest that infection with COVID-19 poses a greater risk than vaccination for those with IPF. Until further data are available, we continue to recommend COVID-19 vaccination for patients with interstitial lung disease. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Prevention of pulmonary infections and acute exacerbations'.)

Risk factors for thunderstorm asthma (July 2022)

"Thunderstorm asthma" refers to asthma exacerbations that occur in the hours after a thunderstorm, especially storms occurring during pollen seasons. The mechanism appears to involve rupture of water-logged pollen grains, which releases allergenic debris that is swept up by strong cross currents and deposited in concentrated form at ground level. In a multicenter study of adults with a past diagnosis of thunderstorm asthma and/or seasonal allergic rhinitis, risk factors for thunderstorm asthma included higher pollen-specific immunoglobulin E levels, eosinophil counts, and fractional exhaled nitric oxide levels as well as asthma that was not optimally controlled [83]. Clinicians and patients should be aware that thunderstorms can precipitate asthma and patients with pollen allergies and asthma should avoid the outdoors during and after thunderstorms occurring during pollen seasons. (See "Trigger control to enhance asthma management", section on 'Thunderstorms'.)


Psychiatric disorders following recovery from COVID-19 (May 2022, Modified September 2022)

Patients who recover from acute COVID-19 are at increased risk for psychiatric disorders, although the risk for some of these disorders may decrease over time. In a large retrospective study, incident psychiatric disorders, including anxiety, depressive, posttraumatic stress, sleep, and substance use disorders, occurred more frequently in patients who survived COVID-19 than in patients without a history of COVID-19 (hazard ratio 1.5) [84]. In another retrospective study of over 1.2 million patients with a history of COVID-19, the risk of psychopathology in the first six months following infection was greater than that among matched controls with a different respiratory infection [85]. However, after another three months, the excess risk of anxiety disorders, insomnia, and mood disorders had diminished. By contrast, a history of COVID-19 was associated with a higher risk of cognitive impairment and psychotic disorders during the entire two-year follow-up period. Patients with COVID-19 can be reassured that eventually the risk of some psychiatric sequelae is no greater than that with other respiratory infections, but some patients with certain post-COVID-19 psychiatric disorders may require psychotherapy and/or pharmacotherapy. (See "COVID-19: Psychiatric illness", section on 'Patients with COVID-19'.)


Role of tocilizumab in patients with polymyalgia rheumatica (October 2022)

While relatively low doses of glucocorticoids are the primary treatment for polymyalgia rheumatica (PMR), interest remains in identifying an effective steroid-sparing agent. In a randomized trial of 100 patients with steroid-dependent PMR, patients who received adjunctive intravenous tocilizumab were more likely to achieve a combined endpoint of lower disease activity score and reduced steroid requirement at 24 weeks (67 versus 31 percent) [86]. Infections were the most frequent adverse events, occurring in 47 and 39 percent of the tocilizumab and placebo groups, respectively. Additional data are needed to confirm these findings and determine the benefits and safety of adjunctive tocilizumab use for PMR. The routine use of steroid-sparing therapies, including adjunctive tocilizumab, is not recommended for patients with PMR. (See "Treatment of polymyalgia rheumatica", section on 'Limited role for glucocorticoid-sparing therapies'.)

Perioperative management of biologic disease-modifying antirheumatic drugs (September 2022)

There is limited evidence to inform the optimal timing of use for biologic disease-modifying antirheumatic drugs (DMARDs) in the perioperative period among patients with systemic rheumatic diseases. In a meta-analysis of cohort studies including over 7300 patients on biologic DMARDs for systemic rheumatic diseases who were undergoing surgery, patients who continued biologics did not appear to be at an increased risk for surgical site infection or delayed wound healing [87]. Stopping biologics prior to surgery, however, was associated with higher rates of disease flares (26 versus 7 percent). These findings are limited by the retrospective and heterogenous nature of the evidence. Our general approach to patients on biologic DMARDs undergoing elective surgery is to withhold the medication at the end of the dosing cycle if disease activity permits. (See "Preoperative evaluation and perioperative management of patients with rheumatic diseases", section on 'Biologic DMARDs'.)


Risk of drug overdose in young people prescribed benzodiazepines for sleep disorders (December 2022)

Prescription database studies indicate that benzodiazepines are commonly prescribed for insomnia, despite risks and the availability of safer options. In a recent cohort study in the United States that included over 90,000 children and young adults (age 10 to 29 years) with a sleep disorder who were prescribed a new insomnia medication, benzodiazepines were associated with increased risk of drug overdose in the next six months compared with alternative insomnia medications (trazodone, hydroxyzine, zolpidem, zaleplon, eszopiclone) [88]. Risk was highest among individuals who had also received an opioid prescription in the preceding three months. We do not prescribe benzodiazepines for insomnia in patients taking opioids or in those with a substance use disorder. (See "Pharmacotherapy for insomnia in adults", section on 'Shared warnings and precautions'.)

Potential benefit of genotyping for variants that affect neutrophil count (September 2022)

Duffy null-associated neutrophil count (DANC) refers to low baseline neutrophil counts due to variants in the ACKR1 gene, which encodes the Duffy chemokine receptor on red blood cells (RBCs). Neutrophil function is normal. DANC is more common in African Americans, and individuals with DANC may inadvertently be underdosed with myelosuppressive medications when low neutrophil counts are misattributed to hematologic toxicity. In a study of 1466 individuals receiving azathioprine, discontinuation was nearly threefold more likely in individuals with DANC [89]. Some experts have suggested that testing for DANC (or for absence of the Duffy antigen on RBCs, which may be faster) could reduce underdosing and lessen racial disparities in outcomes. (See "Overview of pharmacogenomics", section on 'Potential benefits of genotyping'.)

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