Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome.

BACKGROUND: Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. METHODS: Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. RESULTS: Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant. CONCLUSIONS: Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.

Longitudinal Changes in Global Cerebral Blood Flow in Cognitively Normal Older Adults: A Phase-Contrast MRI Study.

BACKGROUND: Characterization of blood supply changes in older individuals is important in understanding brain aging and diseases. However, prior studies largely focused on cross-sectional design, thus change in cerebral blood flow (CBF) could not be assessed on an individual level. PURPOSE: To evaluate longitudinal short-term changes in global CBF in cognitively normal older adults. STUDY TYPE: Prospective, longitudinal, and cohort. POPULATION: One-hundred twenty-seven cognitive-normal participants (mean age 69 ± 7 years, 47 males) underwent serial MRI with an average follow-up time of 2.1 years. FIELD STRENGTH/SEQUENCE: 3 T phase-contrast (PC), three-dimensional magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR) MRI. ASSESSMENT: Total CBF was measured with PC MRI allowing assessment of quantitative flow in four major feeding arteries by a trained radiologist with >3 years' experience (O.K.). Brain volume was obtained from MPRAGE MRI and measured by T1-MultiAtlas MRICloud tool. The ratio between total CBF and brain volume yielded global CBF in mL/100 g/min. White matter hyperintensity (WMH) was measured automatically using a Bayesian probability approach on FLAIR. STATISTICAL TESTS: Linear mixed effect model was used to simultaneously assess cross-sectional age-differences and longitudinal age-changes in CBF. Spearman rank correlation was used to evaluate the relationship between CBF change and WMH progression. A P-value of <0.05 (two-tailed) was considered significant. RESULTS: Global CBF decreased with age at a longitudinal rate of -0.56 mL/100 g/min/year (95% confidence interval [CI]: -1.09, -0.03), compared to a cross-sectional rate of -0.26 mL/100 g/min/year (95% CI: -0.41, -0.11). Changes in CBF were significantly associated with progression of WMH (Spearman rank correlation r = -0.25), as those participants who had a more rapid CBF reduction had greater increases in WMH volumes and the relationship remained significant when adjusting for baseline vascular risk scores. Additionally, age-related changes in whole-brain volume were found to be -0.151%/year (95% CI: -0.186, -0.116). DATA CONCLUSION: These findings suggest that brain aging in older adults is accompanied by a rapid longitudinal reduction in CBF, the rate of which is associated with white matter damage. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Allopregnanolone and depression and anxiety symptoms across the peripartum: an exploratory study.

Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to the limited literature examining ALLO and mood and anxiety at multiple time points across the peripartum. We measured mood and anxiety symptoms and ALLO levels by ELISA at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in N = 73 women with prior histories of mood and/or anxiety disorders and N = 38 healthy controls. Analytic methods included multivariate and logistic regressions with linear mixed effect models. Among all participants (N = 111), higher ALLO levels at W6 were associated with higher depression and anxiety scores: each one unit increase in log ALLO at W6 was associated with a 2.54 point increase on the Edinburgh Postnatal Depression Scale (EPDS) (95% CI: 0.73 to 4.33) and an 8.0 point increase on the Perinatal Anxiety Screening Scale (PASS) (95% CI: 3.82 to 12.6). In addition, the nature of the relationship between log ALLO level and psychological measures changed across time; from T2 to W6 for EPDS, ß = 3.73 (95% CI:1.16, 6.30), p = 0.0045; for PASS ß = 9.78 (95% CI:3.77, 15.79), p = 0.0014); from T3 to W6, for (EPDS, ß = 2.52 (95% CI:0.08, 4.96), p = 0.043; for PASS ß = 7.33 (95% CI:1.63, 13.02), p = 0.018). The relationship of log ALLO to mood and anxiety symptoms was the same among women with and without psychiatric histories. Our exploratory findings indicate that the relationship between ALLO and mood and anxiety symptoms may change across the peripartum.

Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19.

BACKGROUND: Predicting the clinical trajectory of individual patients hospitalized with coronavirus disease 2019 (COVID-19) is challenging but necessary to inform clinical care. The majority of COVID-19 prognostic tools use only data present upon admission and do not incorporate changes occurring after admission. OBJECTIVE: To develop the Severe COVID-19 Adaptive Risk Predictor (SCARP) (https://rsconnect.biostat.jhsph.edu/covid_trajectory/), a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization. DESIGN: Retrospective observational cohort study. SETTINGS: Five hospitals in Maryland and Washington, D.C. PATIENTS: Patients who were hospitalized between 5 March and 4 December 2020 with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed by nucleic acid test and symptomatic disease. MEASUREMENTS: A clinical registry for patients hospitalized with COVID-19 was the primary data source; data included demographic characteristics, admission source, comorbid conditions, time-varying vital signs, laboratory measurements, and clinical severity. Random forest for survival, longitudinal, and multivariate (RF-SLAM) data analysis was applied to predict the 1-day and 7-day risks for progression to severe disease or death for any given day during the first 14 days of hospitalization. RESULTS: Among 3163 patients admitted with moderate COVID-19, 228 (7%) became severely ill or died in the next 24 hours; an additional 355 (11%) became severely ill or died in the next 7 days. The area under the receiver-operating characteristic curve (AUC) for 1-day risk predictions for progression to severe disease or death was 0.89 (95% CI, 0.88 to 0.90) and 0.89 (CI, 0.87 to 0.91) during the first and second weeks of hospitalization, respectively. The AUC for 7-day risk predictions for progression to severe disease or death was 0.83 (CI, 0.83 to 0.84) and 0.87 (CI, 0.86 to 0.89) during the first and second weeks of hospitalization, respectively. LIMITATION: The SCARP tool was developed by using data from a single health system. CONCLUSION: Using the predictive power of RF-SLAM and longitudinal data from more than 3000 patients hospitalized with COVID-19, an interactive tool was developed that rapidly and accurately provides the probability of an individual patient's progression to severe illness or death on the basis of readily available clinical information. PRIMARY FUNDING SOURCE: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

Intraventricular Extension of Supratentorial Intracerebral Hemorrhage: The Modified Graeb Scale Improves Outcome Prediction in Lund Stroke Register.

BACKGROUND/AIMS: The modified Graeb Scale (mGS) is a semi-quantitative method to assess the extension of intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH). The mGS has been shown to prognosticate outcome after ICH in cohorts derived from convenience samples. We evaluated the external validity of mGS in supratentorial ICH-patients from an unselected cohort. METHODS: ICH-patients were included prospectively and consecutively in Lund Stroke Register. Follow-up survival status was obtained from the National Census Office; functional outcome was obtained from the Swedish Stroke Register or medical records. Using multivariate analyses, we examined if mGS was related to 30-day survival or poor functional outcome (modified Rankin Scale ≥4) at 90 days. RESULTS: Of 198 supratentorial ICH-patients, 86 (43%) had IVH (median mGS 12, range 1-28). In multivariate regression analyses, the mGS independently predicted 30-day mortality (per point; OR 1.16; 95% CI 1.06-1.27; p = 0.002) and poor functional outcome (OR 1.11; 95% CI 1.02-1.20; p = 0.011) after ICH. In receiver-operator characteristic analysis, the addition of mGS tended to be associated with a higher prognostic accuracy for survival (area under curve 0.886 vs. not including mGS 0.812; p = 0.053). CONCLUSIONS: The mGS improves outcome prediction after supratentorial ICH beyond other previously established factors in an unselected population.

A randomized feasibility trial of the modified Atkins diet in older adults with mild cognitive impairment due to Alzheimer's disease.

Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action. Methods: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time. Results: A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's D = 0.57, 95% CI: -0.67, 1.33). In the 15 participants (nine MAD, six control) assessed for lipidomic and metabolomic-lipidomics and metabolomics, 13 metabolites and 10 lipids showed significant changes from baseline to 12 weeks, including triacylglycerols (TAGs, 50:5, 52:5, and 52:6), sphingomyelins (SM, 44:3, 46:0, 46:3, and 48:1), acetoacetate, fatty acylcarnitines, glycerol-3-phosphate, and hydroxy fatty acids. Conclusions: Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined a priori, lipidomic and metabolomic analyses indicate significant changes from baseline in circulating lipids and metabolites between MAD and control participants at 12-week postrandomization, and MAD participants showed greater, albeit nonsignificant, improvement in memory.

Hearing Impairment and Physical Activity and Physical Functioning in Older Adults: Baseline Results From the ACHIEVE Trial.

BACKGROUND: Hearing loss is associated with restricted physical activity (PA) and impaired physical functioning, yet the relationship between severity of hearing impairment (HI) and novel PA measures in older adults with untreated HI is not well understood. METHODS: Analyses included 845 participants aged ≥70 years (mean = 76.6 years) with a better-hearing ear pure-tone average (PTA) ≥30 and <70 dB in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study who wore an ActiGraph accelerometer for 7 days. Physical functioning measures included grip strength and the Short Physical Performance Battery (SPPB). Linear regression models estimated the association by HI level (moderate or greater [PTA ≥ 40 dB] vs mild [PTA < 40 dB]) and continuous hearing with total daily activity counts, active minutes/day, activity fragmentation, grip strength, and gait speed. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of poor performance on the SPPB (≤6) and its subtests (≤2). Mixed-effects models estimated differences by HI level in activity by time of day. RESULTS: Participants with moderate or greater HI had poorer physical functioning, particularly balance (OR = 2.17, 95% CI = 1.29-3.67), versus those with mild impairment. There was no association of HI level with activity quantities or fragmentation. For diurnal patterns of activity, participants with moderate or greater HI had fewer activity counts in the afternoon (12:00 pm -05:59 pm). CONCLUSIONS: Older adults with worse hearing had shifted diurnal patterns and poorer balance performance. Exercise programs should be tailored to older adults with different levels of HI to maintain PA and physical functioning, particularly balance control.

Description of the Baseline Audiologic Characteristics of the Participants Enrolled in the Aging and Cognitive Health Evaluation in Elders Study.

PURPOSE: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a randomized clinical trial designed to determine the effects of a best-practice hearing intervention versus a successful aging health education control intervention on cognitive decline among community-dwelling older adults with untreated mild-to-moderate hearing loss. We describe the baseline audiologic characteristics of the ACHIEVE participants. METHOD: Participants aged 70-84 years (N = 977; Mage = 76.8) were enrolled at four U.S. sites through two recruitment routes: (a) an ongoing longitudinal study and (b) de novo through the community. Participants underwent diagnostic evaluation including otoscopy, tympanometry, pure-tone and speech audiometry, speech-in-noise testing, and provided self-reported hearing abilities. Baseline characteristics are reported as frequencies (percentages) for categorical variables or medians (interquartiles, Q1-Q3) for continuous variables. Between-groups comparisons were conducted using chi-square tests for categorical variables or Kruskal-Wallis test for continuous variables. Spearman correlations assessed relationships between measured hearing function and self-reported hearing handicap. RESULTS: The median four-frequency pure-tone average of the better ear was 39 dB HL, and the median speech-in-noise performance was a 6-dB SNR loss, indicating mild speech-in-noise difficulty. No clinically meaningful differences were found across sites. Significant differences in subjective measures were found for recruitment route. Expected correlations between hearing measurements and self-reported handicap were found. CONCLUSIONS: The extensive baseline audiologic characteristics reported here will inform future analyses examining associations between hearing loss and cognitive decline. The final ACHIEVE data set will be publicly available for use among the scientific community. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24756948.

COVID-19 clinical outcomes by patient disability status: A retrospective cohort study.

BACKGROUND: People with disabilities might experience worse clinical outcomes of SARS-CoV-2 infection, but evidence is limited. OBJECTIVE: To investigate if people with disabilities requiring assistance are more likely to experience severe COVID-19 or death. METHODS: Data from the Johns Hopkins COVID-19 Precision Medicine Analytics Platform Registry (JH-CROWN) included 6494 adult patients diagnosed with COVID-19 and admitted between March 4, 2020-October 29, 2021. Severe COVID-19 and death were defined using the occurrence and timing of clinical events. Assistive needs due to disabilities were reported by patients or their proxies upon admission. Multivariable-adjusted Cox proportional hazards models were used to examine the associations between disability status and severe COVID-19 or death. Primary models adjusted for demographics and secondary models additionally adjusted for clinical covariates. RESULTS: In this clinical cohort (47-73 years, 49% female, 39% Black), patients with disabilities requiring assistance had 1.35 times (95% confidence interval [CI]:1.01, 1.81) the hazard of severe COVID-19 among patients <65 years, but not among those ≥65 years, equating to an additional 17.5 severe COVID-19 cases (95% CI:7.7, 28.2) per 100 patients. A lower risk of mortality was found among patients <65 years, but this finding was not robust due to the small number of deaths. CONCLUSIONS: People with disabilities requiring assistance aged <65 years are more likely to develop severe COVID-19. Although our study is limited by using a medical model of disability, these analyses intend to further our understanding of COVID-19 outcomes among people with disabilities. Also, standardized disability data collection within electronic health records is needed.

Association of Carotid Atherosclerosis With Hearing Loss: A Cross-sectional Analysis of the Atherosclerosis Risk in Communities Study.

Objective: To describe the association between midlife carotid atherosclerosis and late-life hearing loss among participants in the Atherosclerosis Risk in Communities (ARIC) study. Design, Setting, and Participants: For this cross-sectional study and temporal analysis of a cohort within the ongoing ARIC prospective cohort study, participants were recruited from 4 communities in the US. The analysis evaluated information on mean carotid intima-media thickness (cIMT), from visit 1 (1987-1989) to visit 4 (1994-1996), carotid plaque presence at visit 4, and audiometric data from visit 6 (2016-2017). The cIMT measures were calculated from ultrasonography recordings by trained readers at the ARIC Ultrasound Reading Center. At each visit, cIMT was computed as the average of 3 segments: the distal common carotid, the carotid artery bifurcation, and the proximal internal carotid arteries. Presence of carotid plaque was determined based on an abnormal wall thickness, shape, or wall texture. Audiometric 4-frequency pure tone average (PTA) was measured and calculated for the better-hearing ear and modeled as a continuous variable. Linear regression estimated the association between cIMT and carotid plaque with hearing, adjusting for age, sex, race and study center, education level, body mass index (calculated as weight in kilograms divided by height in meters squared), smoking status, hypertension, cholesterol levels, diabetes, and exposure to occupational noise. Missing data (exposure and covariates) were imputed with multiple imputation by chained equations. Data analyses were performed from April 6 to July 13, 2022. Main Outcomes and Measures: Hearing loss assessed using 4-frequency (0.5, 1.0, 2.0, and 4.0 kilohertz) PTA for both ears and carotid plaque at visit 4 and mean cIMT from visit 1 to visit 4. Results: Among a total of 3594 participants (mean [SD] age at visit 4, 59.4 [4.6] years; 2146 [59.7%] female; 819 [22.8%] Black and 2775 [77.2%] White individuals), fully adjusted models indicated that an additional 0.1 mm higher mean cIMT was associated with 0.59 dB (95% CI, 0.17 to 1.02 dB) higher PTA. Compared with participants without carotid plaque, plaque presence was associated with 0.63 dB (95% CI, -0.57 to 1.84 dB) higher PTA. Conclusion and Relevance: The findings of this cross-sectional study with temporal analyses of a cohort with the ongoing ARIC study found that subclinical atherosclerosis in midlife was associated with worse hearing in older adulthood. Prevention and control of carotid atherosclerosis during middle age may positively affect the hearing health of older adults.

Prospective Studies Comparing Structured vs Nonstructured Diagnostic Protocol Evaluations Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis.

Importance: Patients meeting the criteria for fever of unknown origin (FUO) can be evaluated with structured or nonstructured approaches, but the optimal diagnostic method is unresolved. Objective: To analyze differences in diagnostic outcomes among patients undergoing structured or nonstructured diagnostic methods applied to prospective clinical studies. Data Sources: PubMed, Embase, Scopus, and Web of Science databases with librarian-generated query strings for FUO, PUO, fever or pyrexia of unknown origin, clinical trial, and prospective studies identified from January 1, 1997, to March 31, 2021. Study Selection: Prospective studies meeting any adult FUO definition were included. Articles were excluded if patients did not precisely fit any existing adult FUO definition or studies were not classified as prospective. Data Extraction and Synthesis: Abstracted data included years of publication and study period, country, setting (eg, university vs community hospital), defining criteria and category outcome, structured or nonstructured diagnostic protocol evaluation, sex, temperature threshold and measurement, duration of fever and hospitalization before final diagnoses, and contribution of potential diagnostic clues, biochemical and immunological serologic studies, microbiology cultures, histologic analysis, and imaging studies. Structured protocols compared with nonstructured diagnostic methods were analyzed using regression models. Main Outcomes and Measures: Overall diagnostic yield was the primary outcome. Results: Among the 19 prospective trials with 2627 unique patients included in the analysis (range of patient ages, 10-94 years; 21.0%-55.3% female), diagnoses among FUO series varied across and within World Health Organization (WHO) geographic regions. Use of a structured diagnostic protocol was not significantly associated with higher odds of yielding a diagnosis compared with nonstructured protocols in aggregate (odds ratio [OR], 0.98; 95% CI, 0.65-1.49) or between Western Europe (Belgium, France, the Netherlands, and Spain) (OR, 0.95; 95% CI, 0.49-1.86) and Eastern Europe (Turkey and Romania) (OR, 0.83; 95% CI, 0.41-1.69). Despite the limited number of studies in some regions, analyses based on the 6 WHO geographic areas found differences in the diagnostic yield. Western European studies had the lowest percentage of achieving a diagnosis. Southeast Asia led with infections at 49.0%. Noninfectious inflammatory conditions were most prevalent in the Western Pacific region (34.0%), whereas the Eastern Mediterranean region had the highest proportion of oncologic explanations (24.0%). Conclusions and Relevance: In this systematic review and meta-analysis, diagnostic yield varied among WHO regions. Available evidence from prospective studies did not support that structured diagnostic protocols had a significantly better rate of achieving a diagnosis than nonstructured protocols. Clinicians worldwide should incorporate geographical disease prevalence in their evaluation of patients with FUO.

Prevalence of Tympanic Membrane Perforations Among Adolescents, Adults, and Older Adults in the United States.

Tympanic membrane (TM) perforations can occur at any age, but limited population-level data are available. Using data from the National Health and Nutrition Examination Survey, we performed a cross-sectional analysis of the prevalence and population estimates for TM perforations among individuals ≥12 years old in the United States. Overall, TM perforations have a prevalence of 2.1% (95% CI, 1.7%-2.6%), corresponding to 5.8 million Americans. Across the life course, older adults have the highest prevalence of TM perforations at 6.1% (95% CI, 4.7%-7.6%), corresponding to nearly 3 million Americans, as opposed to a prevalence of 0.6% (95% CI, 0.3%-0.9%) in adolescents, which equates to 0.2 million Americans. Males and females have a similar prevalence at 2.3% (95% CI, 1.6%-3.0%) among males and 2.0% (95% CI, 1.4%-2.6%) among females. These prevalence and population estimates provide the first US-based population estimates of the burden of TM perforations over the life course.

Self-Reported Dual Sensory Impairment and Subjective Cognitive Complaints Among Older Adults in the 2019 National Health Interview Survey.

PURPOSE: Subjective cognitive complaints (SCCs) are associated with poor quality of life, important for clinical care planning and management, and may predict dementia diagnosis. Dual sensory impairment (DSI) is a risk factor for dementia, but whether DSI is associated with SCCs is unknown. We evaluated whether self-reported DSI is associated with SCCs. METHOD: We performed a cross-sectional analysis of 9,899 community-dwelling respondents aged 60+ years without dementia or depression in the 2019 National Health Interview Survey. Participants self-reported difficulty remembering or concentrating, seeing even when wearing corrective lenses, and hearing even when using a hearing aid. We defined SCCs and sensory impairment for each mode as reporting at least some difficulty. We categorized sensory impairment into no sensory impairment, vision impairment only, hearing impairment only, and DSI. We then estimated weighted prevalence ratios (PRs) of SCCs by impairment category. RESULTS: After weighting (9,899 participants representing a weighted n = 59,261,749), 12% of participants reported vision impairment only, 19% reported hearing impairment only, and 7% reported DSI. Relative to no impairment, after adjustment for potential confounders, vision impairment (PR = 2.07; 95% confidence interval [CI] [1.79, 2.39]), hearing impairment (PR = 2.26; 95% CI [2.00, 2.55]), and DSI (PR = 3.21; 95% CI [2.83, 3.63]) were associated with an increased prevalence of SCCs. CONCLUSIONS: In this nationally representative survey of older Americans, DSI was associated with a threefold increased prevalence of SCCs. Although cross-sectional, these data underscore the importance of assessing multiple impairments as exposures when studying subjective cognition in older adults. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21498711.

Accuracy of self- and proxy-rated hearing among older adults with and without cognitive impairment.

BACKGROUND: Hearing loss is highly prevalent among older adults with cognitive impairment and may exacerbate neuropsychiatric symptoms and affect interactions with others. Although audiometry is the gold standard for measuring hearing, it is not always used in research or clinical settings focused on the care of individuals with cognitive impairment. Subjective assessments of hearing, both self- and proxy-rated, are widespread but may not adequately capture the presence of hearing loss as compared to audiometry. This study investigates the concordance between subjective and objective hearing assessments among older adults with and without cognitive impairment and evaluates factors associated with concordance. METHODS: Participants were a subset of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), a prospective cohort study representing four US communities with adjudicated cognitive diagnoses and audiometric data, totaling 3326 self-rated and 520 proxy-rated hearing assessments. Sensitivity and specificity were calculated, and multivariable logistic regression estimated the magnitude of the association between the concordance of hearing assessments and variables of interest. RESULTS: Sensitivity and specificity for self-rated hearing status were 71.2% and 85.9% among cognitively normal older adults, 61.1% and 84.9% among persons with MCI, and 52.6% and 81.2% among persons with dementia, respectively. For proxy-rated hearing, sensitivity and specificity were 65.7% and 83.3% for persons with MCI and 73.3% and 60.3% for persons with dementia, respectively. Female sex was positively associated with concordance for self-rated hearing assessments. CONCLUSIONS: The low sensitivity of self- and proxy-rated hearing assessments compared to audiometry suggests that hearing loss among older adults with cognitive impairment may go underreported and unaddressed in subjective assessments. Clinicians and researchers should recognize the limitations of using self- and proxy-rated hearing assessments as measures of hearing status and incorporate objective audiometric evaluation whenever possible.

Association of Cigarette Smoking Patterns Over 30 Years With Audiometric Hearing Impairment and Speech-in-Noise Perception: The Atherosclerosis Risk in Communities Study.

IMPORTANCE: The implications of cigarette smoking and smoking cessation for hearing impairment remain unknown. Many studies on this topic have failed to account for attrition among smokers in their findings. OBJECTIVE: To assess the association of cigarette smoking patterns with audiometric and speech-in-noise hearing measures among participants of the Atherosclerosis Risk in Communities Study. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included participants of the Atherosclerosis Risk in Communities Study from 4 US communities. The analysis includes data from visit 1 (1987-1989) through visit 6 (2016-2017); data were analyzed from March 16 through June 25, 2021. Audiometric hearing and speech-in-noise testing was offered to all participants at visit 6. Participants with incomplete audiometric data or missing data for educational level, body mass index, drinking status, a diabetes or hypertension diagnosis, or occupational noise were excluded. In addition, individuals were excluded if they self-reported as having other than Black or White race and ethnicity, or if they self-reported as having Black race or ethnicity and lived in 2 predominantly White communities. MAIN OUTCOMES AND MEASURES: Smoking behavior was classified from visit 1 (1987-1989) to visit 6 (2016-2017) using group-based trajectory modeling based on self-reported smoking status at each clinic visit. Hearing was assessed at visit 6. An audiometric 4-frequency (0.5, 1, 2, 4 kHz) pure-tone average (PTA) was calculated for the better-hearing ear and modeled as a continuous variable. Speech-in-noise perception was assessed via the Quick Speech-in-Noise Test (QuickSIN) and modeled continuously. Attrition during the 30 years of follow-up was addressed by inverse probability of attrition weighting. RESULTS: A total of 3414 participants aged 72 to 94 years (median [IQR] age, 78.8 [76.0-82.9] years; 2032 [59.5%] women) when hearing was measured at visit 6 (2016-2017) were included in the cohort; 766 (22.4%) self-identified as Black and 2648 (77.6%) as White individuals. Study participants were classified into 3 smoking groups based on smoking behavior: never or former smoking at baseline (n = 2911 [85.3%]), quit smoking during the study period (n = 368 [10.8%]), and persistent smoking (n = 135 [4.0%]). In fully adjusted models, persistent smoking vs never or former smoking was associated with an average 2.69 (95% CI, 0.56-4.81) dB higher PTA (worse hearing) and 1.42 (95% CI, -2.29 to -0.56) lower QuickSIN score (worse performance). Associations were stronger when accounting for informative attrition during the study period (3.53 [95% CI, 1.14-5.93] dB higher PTA; 1.46 [95% CI, -2.52 to -0.41] lower QuickSIN scores). Smoking cessation during the study (vs never or former smoking) was not associated with changes in hearing. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, persistent smoking was associated with worse audiometric hearing and speech-in-noise perception. Hearing measures among participants who quit smoking during the study period did not differ from those for never or former smokers, indicating that smoking cessation (as opposed to persistent smoking) may have benefits for hearing health.

Individual Life-Course Socioeconomic Position and Hearing Aid Use in the Atherosclerosis Risk in Communities Study.

BACKGROUND: To measure the association between individual life-course socioeconomic position (SEP) and hearing aid use, we examined childhood and adulthood socioeconomic variables collected at the Atherosclerosis Risk in Communities (ARIC) study baseline visit (1987-1989)/Life Course Socioeconomic Status study (2001-2002) and hearing aid use data collected at visit 6 (2016-2017). METHODS: ARIC is a prospective cohort study of older adults (45-64 years) recruited from 4 U.S. communities. This analysis included a subset of 2 470 participants with hearing loss at visit 6 (≥25 decibels hearing level [dB HL] better-ear) with complete hearing aid use data. Childhood SEP variables included parental education, parental occupation, and parental home ownership. Young and older adulthood SEP variables included income, education, occupation, and home ownership. Each life epoch was assigned a score ranging from 0 to 5 and then summed to calculate the individual cumulative SEP score. Multivariable-adjusted logistic regression was used to estimate the association between individual cumulative SEP and hearing aid use. Missing SEP scores were imputed for participants with incomplete socioeconomic data. RESULTS: Of the 2 470 participants in the analytic cohort (median [interquartile interval] age 79.9 [76.7-84.0], 1 330 [53.8%] women, 450 [18.2%] Black), 685 (27.7%) participants reported hearing aid use. Higher cumulative SEP was positively associated with hearing aid use (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 1.04-1.14), and slightly stronger for childhood (OR = 1.09, 95% CI: 1.00-1.20) than older adulthood SEP score (OR = 1.06, 95% CI: 0.95-1.18). CONCLUSIONS: In this community-based cohort of older adults with hearing loss, higher individual life-course SEP was positively associated with hearing aid use.

Thromboprophylaxis in people hospitalized with COVID-19: Assessing intermediate or standard doses in a retrospective cohort study.

Background and Objectives: Current clinical guidelines recommend thromboprophylaxis for adults hospitalized with coronavirus disease 2019 (COVID-19), yet it is unknown whether higher doses of thromboprophylaxis offer benefits beyond standard doses. Methods: We studied electronic health records from 50 091 adults hospitalized with COVID-19 in the United States between February 2020 and February 2021. We compared standard (enoxaparin 30 or 40 mg/day, fondaparinux 2.5 mg, or heparin 5000 units twice or thrice per day) versus intermediate (enoxaparin 30 or 40 mg twice daily, or up to 1.2 mg/kg of body weight daily, heparin 7500 units thrice per day or heparin 10 000 units twice or thrice per day) thromboprophylaxis. We separately examined risk of escalation to therapeutic anticoagulation, severe disease (first occurrence of high-flow nasal cannula, noninvasive positive pressure ventilation or invasive mechanical ventilation), and death. To summarize risk, we present hazard ratios (HRs) with 95% confidence intervals (CIs) using adjusted time-dependent Cox proportional hazards regression models. Results: People whose first dose was high intensity were younger, more often obese, and had greater oxygen support requirements. Intermediate dose thromboprophylaxis was associated with increased risk of therapeutic anticoagulation (HR, 3.39; 95% CI, 3.22-3.57), severe disease (HR, 1.22; 95% CI, 1.17-1.28), and death (HR, 1.37; 95% CI, 1.21-1.55). Increased risks associated with intermediate-dose thromboprophylaxis persisted in subgroup and sensitivity analyses varying populations and definitions of exposures, outcomes, and covariates. Conclusions: Our findings do not support routine use of intermediate-dose thromboprophylaxis to prevent clinical worsening, severe disease, or death among adults hospitalized with COVID-19.

Hearing loss and risk of depressive symptoms in older adults in the Health ABC study.

Objective: Hearing loss (HL) is highly prevalent among older adults and may lead to increased risk of depressive symptoms. In both cross-sectional and longitudinal analysis, we quantified the association between HL and depressive symptoms, incorporating the variable nature of depressive symptoms and characterizing by race and gender. Methods: Data were from the Health, Aging, and Body Composition study. Depressive symptoms were measured using the Center for Epidemiologic Study Depression Scale short form (CES-D 10), defined as CES-D 10 score ≥10 or treatment for depression. Hearing was defined via four-frequency pure-tone average (PTA) decibel hearing level (dB HL), categorized as normal hearing (PTA ≤25 dB HL), mild HL (PTA26-40 dB HL), and ≥moderate HL (PTA > 40 dB HL). Associations at baseline were quantified using logistic regression, incident depressive symptoms using Cox proportional hazard models, and change in depressive symptoms over time using growth mixture models and multinomial logistic regression. Results: Among 2,089 older adults (1,082 women, 793 Black; mean age 74.0 SD: 2.8), moderate or greater HL was associated with greater odds of concurrent [Odds Ratio (OR):2.45, 95% CI:1.33, 4.51] and incident depressive symptoms [Hazard Ratio (HR):1.26, 95% CI:1.00, 1.58]. Three depressive symptom trajectory patterns were identified from growth mixture models: low, moderate increasing, and borderline high depressive symptom levels. Those with moderate or greater HL were more likely to be in the borderline high depressive-symptom trajectory class than the low trajectory class [Relative Risk Ratio (RRR):1.16, 95% CI:1.01, 1.32]. Conclusions: HL was associated with greater depressive symptoms. Although findings were not statistically significantly different by gender and race, estimates were generally stronger for women and Black participants. Investigation of psychosocial factors and amelioration by hearing aid use could have significant benefit for older adults' quality of life.