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These Annals of Internal Medicine results only contain recent articles.

Major Update 2: Antibody Response and Risk for Reinfection After SARS-CoV-2 Infection—Final Update of a Living, Rapid Review

Background: The durability of the antibody response after SARS-CoV-2 infection and the role of antibodies in protection against reinfection are unclear. Purpose: To synthesize evidence on the SARS-CoV-2 antibody response and reinfection risk with a focus on gaps identified in our prior reports. Data Sources: MEDLINE (Ovid), EMBASE, CINAHL, World Health Organization Research Database, and reference lists from 16 December 2021 through 8 July 2022, with surveillance through 22 August 2022. Study Selection: English-language, cohort studies evaluating IgG antibody duration at least 12 months after SARS-CoV-2 infection, the antibody response among immunocompromised adults, predictors of nonseroconversion, and reinfection risk. Data Extraction: Two investigators sequentially extracted study data and rated quality. Data Synthesis: Most adults had IgG antibodies after SARS-CoV-2 infection at time points greater than 12 months (low strength of evidence [SoE]). Although most immunocompromised adults develop antibodies, the overall proportion with antibodies is lower compared with immunocompetent adults (moderate SoE for organ transplant patients and low SoE for patients with cancer or HIV). Prior infection provided substantial, sustained protection against symptomatic reinfection with the Delta variant (high SoE) and reduced the risk for severe disease due to Omicron variants (moderate SoE). Prior infection was less protective against reinfection with Omicron overall (moderate SoE), but protection from earlier variants waned rapidly (low SoE). Limitation: Single review for abstract screening and sequential review for study selection, data abstraction, and quality assessment. Conclusion: Evidence for a sustained antibody response to SARS-CoV-2 infection is considerable for both Delta and Omicron variants. Prior infection protected against reinfection with both variants, but, for Omicron, protection was weaker and waned rapidly. This information may have limited clinical applicability as new variants emerge. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098)

Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine–Topiramate to Prevent Exposure During Pregnancy

Background: The U.S. Food and Drug Administration approved phentermine–topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. Objective: To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine–topiramate compared with topiramate or other antiobesity medications (AOMs). Design: Retrospective cohort study. Setting: Nationwide health insurance claims database. Participants: Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. Measurements: Patients initiated use of phentermine–topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion–naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. Results: A total of 156 280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine–topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine–topiramate versus topiramate. Both outcomes were similarly lower for phentermine–topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine–topiramate users. Limitations: Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. Conclusion: Prenatal exposure seemed to be significantly lower among phentermine–topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. Primary Funding Source: None.

Challenged Urine Bicarbonate Excretion as a Measure of Cystic Fibrosis Transmembrane Conductance Regulator Function in Cystic Fibrosis

Background: In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function. Objective: To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor–induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults. Design: Prospective observational study. Setting: Cystic fibrosis clinic, Aarhus University Hospital, Denmark. Patients: Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021. Measurements: Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment. Results: At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%. Limitation: Single-center study without a placebo-controlled group. Conclusion: Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis. Primary Funding Source: Innovation Fund Denmark.

Long-Term Changes in the Size of Pituitary Microadenomas

Background: The estimated prevalence of pituitary lesions is 10% to 38.5% in radiologic studies. However, how frequently these incidental lesions should be monitored by serial pituitary magnetic resonance imaging (MRI) remains unclear. Objective: To evaluate changes in pituitary microadenomas over time. Design: Retrospective, longitudinal cohort study. Setting: Mass General Brigham, Boston, Massachusetts. Patients: Evidence of pituitary microadenoma from MRI. Measurements: Dimensions of pituitary microadenomas. Results: During the study period (from 2003 to 2021), 414 patients with pituitary microadenomas were identified. Of the 177 patients who had more than 1 MRI, 78 had no change in the size of the microadenoma over time, 49 had an increase in size, 34 had a decrease in size, and 16 had both an increase and decrease in size. By linear mixed model analysis, the estimated slope was 0.016 mm/y (95% CI, −0.037 to 0.069). In the subgroup analysis, pituitary adenomas with a baseline size of 4 mm or less tended to increase in size. The estimated slope was 0.09 mm/y (CI, 0.020 to 0.161). In contrast, in the subgroup with baseline tumor size greater than 4 mm, the size tended to decrease. The estimated slope was −0.063 mm/y (CI, −0.141 to 0.015). Limitation: Retrospective cohort, some patients were lost to follow-up for unknown reasons, and data were limited to local large institutions. Conclusion: During the study period, approximately two thirds of the microadenomas remained unchanged or decreased in size. The growth, if any, was slow. These findings suggest that less frequent pituitary MRI surveillance for patients with incidental pituitary microadenomas may be safe. Primary Funding Source: None.

Ticagrelor–Aspirin Versus Clopidogrel–Aspirin Among CYP2C19 Loss-of-Function Carriers With Minor Stroke or Transient Ischemic Attack in Relation to Renal Function: A Post Hoc Analysis of the CHANCE-2 Trial

Background: Evidence on the risk–benefit ratio of dual antiplatelet therapies among patients with stroke and impaired renal function is limited and inconsistent. Objective: To investigate the effect of renal function on the efficacy and safety of ticagrelor–aspirin versus clopidogrel–aspirin treatment. Design: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04078737) Setting: 202 centers in China. Patients: CYP2C19 loss-of-function allele carriers with minor stroke or transient ischemic attack. Intervention: Ticagrelor–aspirin and clopidogrel–aspirin. Measurements: Renal function was evaluated by estimated glomerular filtration rate (eGFR) levels. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days, respectively. Results: Among 6378 patients, 4050 (63.5%) had normal (eGFR ≥90 mL/min/1.73 m2), 2010 (31.5%) had mildly decreased (eGFR 60 to 89 mL/min/1.73 m2), and 318 (5.0%) had moderately to severely decreased (eGFR <60 mL/min/1.73 m2) renal function. The corresponding differences in recurrent stroke between ticagrelor–aspirin and clopidogrel–aspirin for normal, mildly decreased, and moderately to severely decreased renal function was −2.8 percentage points (95% CI, −4.4 to −1.3 percentage points) (hazard ratio [HR], 0.63 [CI, 0.49 to 0.81]), −0.2 percentage point (CI, −2.4 to 2.0 percentage points) (HR, 0.98 [CI, 0.69 to 1.39]), and 3.7 percentage points (CI, −2.3 to 10.1 percentage points) (HR, 1.31 [CI, 0.48 to 3.55]), respectively. Rates of severe or moderate bleeding did not substantially differ by treatment assignments across eGFR categories. Limitation: Renal function was only evaluated by using eGFR, and the proportion of patients with severely decreased renal function was low. Conclusion: Patients with normal, rather than impaired, renal function received greater benefit from ticagrelor–aspirin versus clopidogrel–aspirin. Primary Funding Source: Ministry of Science and Technology of the People's Republic of China.

Left Atrial Mechanical Dysfunction and the Risk for Ischemic Stroke in People Without Prevalent Atrial Fibrillation or Stroke: A Prospective Cohort Study: Annals of Internal Medicine: Vol 176, No 1

Background: Atrial myopathy—characterized by changes in left atrial function and size—may precede and promote atrial fibrillation (AF) and cardiac thromboembolism. In people without prior AF or stroke, whether analysis of left atrial function and size can improve ischemic stroke prediction is unknown. Objective: To evaluate the association of echocardiographic left atrial function (reservoir, conduit, and contractile strain) and left atrial size (left atrial volume index) with ischemic stroke and determine whether these measures can improve the stroke prediction achieved by CHA2DS2-VASc score variables. Design: Prospective cohort study. Setting: ARIC (Atherosclerosis Risk in Communities) study. Participants: 4917 ARIC participants without prevalent stroke or AF. Measurements: Ischemic stroke events (2011 to 2019) were adjudicated by physicians. Left atrial strain was measured using speckle-tracking echocardiography. Results: Over 5 years, the cumulative incidences of ischemic stroke in the lowest quintiles of left atrial reservoir, conduit, and contractile strain were 2.99% (95% CI, 1.89% to 4.09%), 3.18% (CI, 2.14% to 4.22%), and 2.15% (CI, 1.09% to 3.21%), respectively, and that of severe left atrial enlargement was 1.99% (CI, 0.23% to 3.75%). On the basis of the Akaike information criterion, left atrial reservoir strain plus CHA2DS2-VASc variables was the best predictive model. With the addition of left atrial reservoir strain to CHA2DS2-VASc variables, 11.6% of the 112 participants with stroke after 5 years were reclassified to higher risk categories and 1.8% to lower risk categories. Among the 4805 participants who did not develop stroke, 12.2% were reclassified to lower and 12.7% to higher risk categories. Decision curve analysis showed a predicted net benefit of 1.34 per 1000 people at a 5-year risk threshold of 5%. Limitation: Underascertainment of subclinical AF. Conclusion: In people without prior AF or stroke, when added to CHA2DS2-VASc variables, left atrial reservoir strain improves stroke prediction and yields a predicted net benefit, as shown by decision curve analysis. Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Long-Term Health Consequences After Ovarian Removal at Benign Hysterectomy: A Nationwide Cohort Study: Annals of Internal Medicine: Vol 176, No 5

Background: More evidence is needed to substantiate current recommendations about removing ovaries during hysterectomy for benign conditions. Objective: To compare long-term outcomes in women with and without bilateral salpingo-oophorectomy (BSO) during hysterectomy for benign conditions. Design: Emulated target trial using data from a population-based cohort. Setting: Women in Denmark aged 20 years or older during 1977 to 2017. Participants: 142 985 women with hysterectomy for a benign condition, 22 974 with BSO and 120 011 without. Intervention: Benign hysterectomy with or without BSO. Measurements: The primary outcomes were overall hospitalization for cardiovascular disease (CVD), overall cancer incidence, and all-cause mortality through December 2018. Results: Compared with women without BSO, women with BSO who were younger than 45 years at surgery had a higher 10-year cumulative risk for hospitalization for CVD (risk difference [RD], 1.19 percentage points [95% CI, 0.09 to 2.43 percentage points]). Women with BSO had a higher 10-year cumulative risk for cancer for ages 45 to 54 years (RD, 0.73 percentage point [CI, 0.05 to 1.38 percentage points]), 55 to 64 years (RD, 1.92 percentage points [CI, 0.69 to 3.25 percentage points]), and 65 years or older (RD, 2.54 percentage points [CI, 0.91 to 4.25 percentage points]). Women with BSO had higher 10-year mortality in all age groups, although the differences were statistically significant only for ages 45 to 54 years (RD, 0.79 percentage point [CI, 0.27 to 1.30 percentage points]). The mortality at 20 years was inconsistent with that at 10 years in women aged 65 years or older. Limitation: Age was a proxy for menopausal status. Conclusion: The authors find that these results support current recommendations for conserving ovaries in premenopausal women without a high risk for ovarian cancer and suggest a cautious approach in postmenopausal women. Primary Funding Source: The Danish Cancer Society's Scientific Committee and the Mermaid Project.

Prevalence and Characteristics of Adrenal Tumors in an Unselected Screening Population: A Cross-Sectional Study: Annals of Internal Medicine: Vol 175, No 10

Background: With the widespread use of advanced imaging technology, adrenal tumors are increasingly being identified. Objective: To investigate the prevalence and characteristics of adrenal tumors in an unselected screening population in China. Design: Cross-sectional study. (ClinicalTrials.gov: NCT04682938) Setting: A health examination center in China. Patients: Adults having an annual checkup were invited to be screened for adrenal tumors by adrenal computed tomography. Measurements: The participants with adrenal tumors had further evaluation for malignancy risk and adrenal function. Results: A total of 25 356 participants were screened, 351 of whom were found to have adrenal tumors, for a prevalence of 1.4%. The prevalence increased with age, from 0.2% in participants aged 18 to 25 years to 3.2% in those older than 65 years. Among 351 participants with adrenal tumors, 337 were diagnosed with an adrenocortical adenoma, 14 with another benign nodule, and none with a malignant mass. In 212 participants with an adenoma who completed endocrine testing, 69.3% were diagnosed with a nonfunctioning adenoma, 18.9% with cortisol autonomy, 11.8% with primary aldosteronism, and none with pheochromocytoma. Proportions of nonfunctioning adenomas were similarly high in various age groups (72.2%, 67.8%, and 72.2% in those aged <46, 46 to 65, and ≥66 years, respectively). Limitation: Only 212 of 337 participants with an adrenocortical adenoma had endocrine testing. Conclusion: The prevalence of adrenal tumors in the general adult screening population is 1.4%, and most of these tumors are nonfunctioning regardless of patient age. Cortisol and aldosterone secretion are the main causes of functional adenomas. Primary Funding Source: National Key Research and Development Program of China and National Natural Science Foundation of China.