Accuracy of Biomarker Testing for Neuropathologically Defined Alzheimer Disease in Older Adults With Dementia: A Systematic Review: Annals of Internal Medicine: Vol 172, No 10

Background: Biomarker accuracy for Alzheimer disease (AD) is uncertain. Purpose: To summarize evidence on biomarker accuracy for classifying AD in older adults with dementia. Data Sources: Electronic bibliographic databases (searched from January 2012 to November 2019 for brain imaging and cerebrospinal fluid [CSF] tests and from inception to November 2019 for blood tests), ClinicalTrials.gov (to November 2019), and systematic review bibliographies. Study Selection: English-language studies evaluating the accuracy of brain imaging, CSF testing, or blood tests for distinguishing neuropathologically defined AD from non-AD among older adults with dementia. Studies with low or medium risk of bias were analyzed. Data Extraction: Two reviewers rated risk of bias. One extracted data; the other verified accuracy. Data Synthesis: Fifteen brain imaging studies and 9 CSF studies met analysis criteria. Median sensitivity and specificity, respectively, were 0.91 and 0.92 for amyloid positron emission tomography (PET), 0.89 and 0.74 for 18F-labeled fluorodeoxyglucose (18F-FDG) PET, 0.64 and 0.83 for single-photon emission computed tomography, and 0.91 and 0.89 for medial temporal lobe atrophy on magnetic resonance imaging (MRI). Individual CSF biomarkers and ratios had moderate sensitivity (range, 0.62 to 0.83) and specificity (range, 0.53 to 0.69); in the few direct comparisons, β-amyloid 42 (Aβ42)/phosphorylated tau (p-tau) ratio, total tau (t-tau)/Aβ42 ratio, and p-tau appeared more accurate than Aβ42 and t-tau alone. Single studies suggested that amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation. Limitations: Studies were small, biomarker cut points and neuropathologic AD were inconsistently defined, and methods with uncertain applicability to typical clinical settings were used. Few studies directly compared biomarkers, assessed test combinations, evaluated whether biomarkers improved classification accuracy when added to clinical evaluation, or reported harms. Conclusion: In methodologically heterogeneous studies of uncertain applicability to typical clinical settings, amyloid PET, 18F-FDG PET, and MRI were highly sensitive for neuropathologic AD. Amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897)

Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 172, No 10

Background: Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain. Purpose: To summarize evidence on the effects of prescription drugs and supplements for CATD treatment. Data Sources: Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies. Study Selection: English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD). Data Extraction: Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy. Data Synthesis: Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, −0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes. Limitation: Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials. Conclusion: Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897)

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Age-Related Low Testosterone

Caring for the Transgender Patient: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 172, No 3

The term transgender refers to persons whose gender identity is different from that recorded at birth. Similar to other marginalized populations, transgender patients commonly experience discrimination in the health care setting, and they may not have access to medical professionals who can provide competent care. In addition to primary medical and preventive health care, transgender patients need access to gender-affirming interventions, including hormone therapy and surgeries. In 2017, the Endocrine Society updated its clinical practice guideline for the care of transgender persons on the basis of the best available evidence from systematic reviews and individual studies. Among its general requirements for adolescents and recommendations for adults were the following: Involvement of a mental health professional who is knowledgeable about the diagnostic criteria for gender dysphoria and criteria for gender-affirming treatment, has training and experience in assessing psychopathology, and is willing to participate in ongoing care. Hormone therapy should be offered to transgender adult patients, with levels maintained within the normal range for gender identity and treatment appropriately monitored. Clinicians involved in the care of transgender adult patients should be knowledgeable about diagnostic criteria for gender dysphoria/gender incongruence, the use of medical and surgical gender-affirming interventions, and appropriate monitoring for reproductive organ cancer risk. Here, 2 clinicians with expertise in this area debate whether psychological evaluation is warranted in a transgender patient requesting gender-affirming hormones or surgery, the potential risks and benefits of estrogen therapy, and the role of the primary care practitioner in the care of transgender persons.

Rifabutin-Based Triple Therapy (RHB-105) for Helicobacter pylori Eradication: A Double-Blind, Randomized, Controlled Trial: Annals of Internal Medicine: Vol 172, No 12

Background: Although consensus supports eradication of Helicobacter pylori infections, antimicrobial resistance has substantially reduced eradication rates with most current therapies. Objective: To assess the effectiveness of a novel rifabutin-based therapy (RHB-105) for H pylori eradication. Design: Phase 3, double-blind trial (ERADICATE Hp2). (ClinicalTrials.gov: NCT03198507) Setting: 55 clinical research sites in the United States. Participants: 455 treatment-naive adults with epigastric discomfort and confirmed H pylori infection. Intervention: RHB-105 (amoxicillin, 3 g; omeprazole, 120 mg; and rifabutin, 150 mg) versus active comparator (amoxicillin, 3 g, and omeprazole, 120 mg), given as 4 capsules every 8 hours for 14 days. Measurements: Between-group difference for H pylori eradication rate, demonstrated by 13C urea breath test 4 weeks after treatment, analyzed by using the χ2 test. Results: In the intention-to-treat population, the eradication rate was higher with RHB-105 than with the active comparator (228 vs. 227 patients, respectively; 83.8% [95% CI, 78.4% to 88.0%] vs. 57.7% [95% CI, 51.2% to 64.0%]; P < 0.001). Eradication rates were unaffected by resistance to clarithromycin or metronidazole. No rifabutin resistance was detected. The most commonly reported adverse events (incidence ≥5%) were diarrhea (10.1% with RHB-105 vs. 7.9% with active comparator), headache (7.5% vs. 7.0%), and nausea (4.8% vs. 5.3%). Limitation: Persons of Asian descent were excluded because of their higher prevalence of poor cytochrome P450 2C19 metabolizers. Conclusion: These findings suggest potential for RHB-105 as first-line empirical H pylori therapy, addressing an unmet need in the current environment of increasing antibiotic resistance. Primary Funding Source: RedHill Biopharma Ltd.

Optimal Panel Size: Are We Asking the Right Question?

Nonpharmacologic and Pharmacologic Management of Acute Pain From Non–Low Back, Musculoskeletal Injuries in Adults: A Clinical Guideline From the American College of Physicians and American Academy of Family Physicians

Description: The American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) developed this guideline to provide clinical recommendations on nonpharmacologic and pharmacologic management of acute pain from non–low back, musculoskeletal injuries in adults in the outpatient setting. The guidance is based on current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences. This guideline does not address noninvasive treatment of low back pain, which is covered by a separate ACP guideline that has also been endorsed by AAFP. Methods: This guideline is based on a systematic evidence review on the comparative efficacy and safety of nonpharmacologic and pharmacologic management of acute pain from non–low back, musculoskeletal injuries in adults in the outpatient setting and a systematic review on the predictors of prolonged opioid use. We evaluated the following clinical outcomes using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system: pain (at ≤2 hours and at 1 to 7 days), physical function, symptom relief, treatment satisfaction, and adverse events. Target Audience and Patient Population: The target audience is all clinicians, and the target patient population is adults with acute pain from non–low back, musculoskeletal injuries. Recommendation 1: ACP and AAFP recommend that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with topical nonsteroidal anti-inflammatory drugs (NSAIDs) with or without menthol gel as first-line therapy to reduce or relieve symptoms, including pain; improve physical function; and improve the patient's treatment satisfaction (Grade: strong recommendation; moderate-certainty evidence). Recommendation 2a: ACP and AAFP suggest that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with oral NSAIDs to reduce or relieve symptoms, including pain, and to improve physical function, or with oral acetaminophen to reduce pain (Grade: conditional recommendation; moderate-certainty evidence). Recommendation 2b: ACP and AAFP suggest that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with specific acupressure to reduce pain and improve physical function, or with transcutaneous electrical nerve stimulation to reduce pain (Grade: conditional recommendation; low-certainty evidence). Recommendation 3: ACP and AAFP suggest against clinicians treating patients with acute pain from non–low back, musculoskeletal injuries with opioids, including tramadol (Grade: conditional recommendation; low-certainty evidence).

Predictors of Prolonged Opioid Use After Initial Prescription for Acute Musculoskeletal Injuries in Adults: A Systematic Review and Meta-analysis of Observational Studies: Annals of Internal Medicine: Vol 173, No 9

Background: Opioids are frequently prescribed for acute musculoskeletal injuries and may result in long-term use and consequent harms. Purpose: To explore factors associated with persistent opioid use after its prescription for acute musculoskeletal injury. Data Sources: Searches of multiple electronic databases, without language restrictions, from inception to 6 January 2020, and reference lists of selected articles. Study Selection: Observational studies of adults with opioid prescriptions for outpatient acute musculoskeletal injuries, in an adjusted model, that explored risk factors for prolonged use. Data Extraction: 6 reviewers, working in pairs, independently extracted data, rated the quality of studies, and evaluated the certainty of evidence. Data Synthesis: 14 cohorts with 13 263 393 participants were included. The overall prevalence of prolonged opioid use after musculoskeletal injury for high-risk populations (that is, patients receiving workers' compensation benefits, Veterans Affairs claimants, or patients with high rates of concurrent substance use disorder) was 27% (95% CI, 18% to 37%). The prevalence among low-risk populations was 6% (CI, 4% to 8%; P for interaction < 0.001). Moderate-certainty evidence showed increased odds of persistent opioid use with older age (absolute risk increase [ARI] for every 10-year increase, 1.1% [CI, 0.7% to 1.5%]) and physical comorbidity (ARI, 0.9% [CI, 0.1% to 1.7%]). Low-certainty evidence suggested increased risk for persistent opioid use with past or current substance use disorder (ARI, 10.5% [CI, 4.2% to 19.8%]), prescriptions lasting more than 7 days (median ARI, 4.5%), and higher morphine milligram equivalents per day. Limitation: Sparse, heterogeneous data with suboptimal adjustment for potential confounders. Conclusion: Avoiding prescribing opioids for acute musculoskeletal injuries to patients with past or current substance use disorder, and restricting duration to 7 days or less and using lower doses when they are prescribed, are potentially important targets to reduce rates of persistent opioid use. Primary Funding Source: National Safety Council. (PROSPERO: CRD42018104968)

The Management of Chronic Insomnia Disorder and Obstructive Sleep Apnea: Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines

Description: In September 2019, the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD) approved a new joint clinical practice guideline for assessing and managing patients with chronic insomnia disorder and obstructive sleep apnea (OSA). This guideline is intended to give health care teams a framework by which to screen, evaluate, treat, and manage the individual needs and preferences of VA and DoD patients with either of these conditions. Methods: In October 2017, the VA/DoD Evidence-Based Practice Work Group initiated a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature, created three 1-page algorithms, and advanced 41 recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Recommendations: This synopsis summarizes the key recommendations of the guideline in 3 areas: diagnosis and assessment of OSA and chronic insomnia disorder, treatment and management of OSA, and treatment and management of chronic insomnia disorder. Three clinical practice algorithms are also included.

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