Head-to-Head Comparison of Tau and Amyloid Positron Emission Tomography Visual Reads for Differential Diagnosis of Neurodegenerative Disorders: An International, Multicenter Study.

OBJECTIVE: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). METHODS: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). RESULTS: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). INTERPRETATION: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024.

Exposure to autoimmune disorders increases Alzheimer's disease risk in a multi-site electronic health record analysis.

Molecular studies of Alzheimer's disease (AD) implicate potential links between autoimmunity and AD, but the underlying clinical relationships between these conditions remain poorly understood. Electronic health records (EHRs) provide an opportunity to determine the clinical risk relationship between autoimmune disorders and AD and understand whether specific disorders and disorder subtypes affect AD risk at the phenotypic level in human populations. We evaluated relationships between 26 autoimmune disorders and AD across retrospective observational case-control and cohort study designs in the EHR systems at UCSF and Stanford. We quantified overall and sex-specific AD risk effects that these autoimmune disorders confer. We identified significantly increased AD risk in autoimmune disorder patients in both study designs at UCSF and at Stanford. This pattern was driven by specific autoimmunity subtypes including endocrine, gastrointestinal, dermatologic, and musculoskeletal disorders. We also observed increased AD risk from autoimmunity in both women and men, but women with autoimmune disorders continued to have a higher AD prevalence than men, indicating persistent sex-specificity. This study identifies autoimmune disorders as strong risk factors for AD that validate across several study designs and EHR databases. It sets the foundation for exploring how underlying autoimmune mechanisms increase AD risk and contribute to AD pathogenesis.

A Prospective Association Between Sensory Impairment and Cognitive Performance Among Older Community-Dwelling Adults: The Role of Depressive Symptoms.

We examined whether vision impairment (VI) and hearing impairment (HI) and dual sensory impairment (DSI) affect cognitive performance and whether depression mediates that effect. We examined 55,340 participants from the Survey of Health, Aging and Retirement in Europe, which assessed 32,325 participants in 2011 (baseline, Time 1), 2015 (follow-up, Time 2), sociodemographic data and health factors, self-reported VI, HI, and DSI at baseline, depression, and cognitive performance after four years. A multiple mediator model was tested using bootstrapping and resampling. At baseline, 22.9% had VI, 10.2% HI, and 10.4% had DSI. We found a significant negative association between VI (b = -0.023, p = .001) and DSI (b = -0.083, p = .001) and cognitive performance; both were also associated with depression, which was linked with poor cognition. VI or DSI among older adults are associated with poor cognitive function directly and indirectly by increasing depression symptoms.

Examining the relation between bilingualism and age of symptom onset in frontotemporal dementia.

Bilingualism is thought to confer advantages in executive functioning, thereby contributing to cognitive reserve and a later age of dementia symptom onset. While the relation between bilingualism and age of onset has been explored in Alzheimer's dementia, there are few studies examining bilingualism as a contributor to cognitive reserve in frontotemporal dementia (FTD). In line with previous findings, we hypothesized that bilinguals with behavioral variant FTD would be older at symptom onset compared to monolinguals, but that no such effect would be found in patients with nonfluent/agrammatic variant primary progressive aphasia (PPA) or semantic variant PPA. Contrary to our hypothesis, we found no significant difference in age at symptom onset between monolingual and bilingual speakers within any of the FTD variants, and there were no notable differences on neuropsychological measures. Overall, our results do not support a protective effect of bilingualism in patients with FTD-spectrum disease in a U.S. based cohort.

Predictors of weight and waist gain in US South Asians: Findings from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.

Background: Weight and waist gain are significant concerns in adulthood. Both weight and waist gain are particularly important among South Asians, a high-risk group known to develop chronic cardiometabolic complications at any body mass index compared to other racial and ethnic groups. Objective: The aim of this study was to investigate factors predicting weight and waist gain in a longitudinal cohort of US South Asians, a high-risk group for developing obesity-related complications. Methods: We used data from Mediators of Atherosclerosis in South Asians Living in America study (MASALA) exam 1 (2010-2013) and exam 2 (2015-2018), with a mean 4.8 years of follow-up. Results: Of 634 participants studied (42.7% women, mean age 55 years, BMI 25.7 kg/m2, weight 70.4 kg at exam 1), 34.7% had gained ≥5% weight and 32.3% gained ≥5% waist at exam 2. In the adjusted models, older age, higher number of years of US residence, and having diabetes were associated with lower odds of weight gain; being female and having higher adiponectin were associated with higher odds of weight gain. Being female, employed full or part time, or retired were associated with lower odds of waist gain. Being single, separated/divorced, having a higher leptin and a higher C-reactive protein level were associated with higher odds of waist gain. Conclusions: South Asian subgroups with higher risk of weight and/or waist gain may benefit from targeted interventions to improve health outcomes.

A Machine Learning System to Indicate Diagnosis of Idiopathic Pulmonary Fibrosis Non-Invasively in Challenging Cases.

Radiologic usual interstitial pneumonia (UIP) patterns and concordant clinical characteristics define a diagnosis of idiopathic pulmonary fibrosis (IPF). However, limited expert access and high inter-clinician variability challenge early and pre-invasive diagnostic sensitivity and differentiation of IPF from other interstitial lung diseases (ILDs). We investigated a machine learning-driven software system, Fibresolve, to indicate IPF diagnosis in a heterogeneous group of 300 patients with interstitial lung disease work-up in a retrospective analysis of previously and prospectively collected registry data from two US clinical sites. Fibresolve analyzed cases at the initial pre-invasive assessment. An Expert Clinical Panel (ECP) and three panels of clinicians with varying experience analyzed the cases for comparison. Ground Truth was defined by separate multi-disciplinary discussion (MDD) with the benefit of surgical pathology results and follow-up. Fibresolve met both pre-specified co-primary endpoints of sensitivity superior to ECP and significantly greater specificity (p = 0.0007) than the non-inferior boundary of 80.0%. In the key subgroup of cases with thin-slice CT and atypical UIP patterns (n = 124), Fibresolve's diagnostic yield was 53.1% [CI: 41.3-64.9] (versus 0% pre-invasive clinician diagnostic yield in this group), and its specificity was 85.9% [CI: 76.7-92.6%]. Overall, Fibresolve was found to increase the sensitivity and diagnostic yield for IPF among cases of patients undergoing ILD work-up. These results demonstrate that in combination with standard clinical assessment, Fibresolve may serve as an adjunct in the diagnosis of IPF in a pre-invasive setting.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Electric Bicycle Injuries and Hospitalizations.

This cross-sectional study investigates injury trends associated with electric bicycles in the US from 2017 to 2022.

Leveraging electronic health records and knowledge networks for Alzheimer's disease prediction and sex-specific biological insights.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

More than a piece of cake: Noun classifier processing in primary progressive aphasia.

INTRODUCTION: Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. METHODS: We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. RESULTS: Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. DISCUSSION: This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. HIGHLIGHTS: Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis.

BACKGROUND: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort. METHODS: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2. FINDINGS: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I2=77%), 60% (56-64; I2=35%) were women, and 80% (72-89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid ß in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I2=89%), Lewy body disease (44%, 25-62; I2=77%), and cerebrovascular injury (42%, 24-60; I2=88%). INTERPRETATION: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity. FUNDING: None.

Estimated effects of amyloid reduction on cognitive change: A Bayesian update across a range of priors.

INTRODUCTION: The results of the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials have rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results. METHODS: We used publicly available data from the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR-SB) score. A range of prior positions were then updated according to Bayes' theorem using these estimates. RESULTS: After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB score. DISCUSSION: For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side-effect risk. HIGHLIGHTS: The results of recent trials of amyloid-targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid-targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid-targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects.

How older men live with stress urinary incontinence: Patient experience and navigation to treatment.

OBJECTIVES: To explore the context in which older men navigate treatment for stress urinary incontinence (SUI) following prostate surgery by characterizing lived experience of men with symptomatic SUI. SUBJECTS/PATIENTS AND METHODS: Mixed method study using surveys and semistructured interviews to examine a cohort of men who underwent evaluation for treatment of postprostatectomy SUI. RESULTS: Thirty-six men were interviewed after consultation for SUI and 31 had complete quantitative clinical data. Twenty-six underwent surgery and 10 chose no surgical intervention. In qualitative interviews, respondents experienced substantial decline in quality of life due to incontinence citing concerns associated with use of pads and worrying about incontinence. Most patients reported "workarounds"-efforts to mitigate or manage incontinence including Kegels, physical therapy, and garments. Participants also reported lifestyle changes including less strenuous physical activity, less sexual activity, and/or fewer social gatherings. Patients then described a "breaking point" where incontinence workarounds were no longer sufficient. After seeking evaluation, men described challenges in exploring treatment for SUI, including access to care and provider knowledge of treatment options. CONCLUSION: In a novel study of patients living with SUI a predictable lived experience was observed that culminated in a desire for change or "breaking point." In all men, this led to treatment-seeking behaviors and for many it led to SUI intervention. Despite effective treatments, patients continue to meet barriers gaining access to SUI evaluation and treatment.

Association between language discordance and unplanned hospital readmissions or emergency department revisits: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Studies conflict about whether language discordance increases rates of hospital readmissions or emergency department (ED) revisits for adult and paediatric patients. The literature was systematically reviewed to investigate the association between language discordance and hospital readmission and ED revisit rates. DATA SOURCES: Searches were performed in PubMed, Embase and Google Scholar on 21 January 2021, and updated on 27 October 2022. No date or language limits were used. STUDY SELECTION: Articles that (1) were peer-reviewed publications; (2) contained data about patient or parental language skills and (3) included either unplanned hospital readmission or ED revisit as one of the outcomes, were screened for inclusion. Articles were excluded if: unavailable in English; contained no primary data or inaccessible in a full-text form (eg, abstract only). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data using Preferred Reporting Items for Systematic Reviews and Meta-Analyses-extension for scoping reviews guidelines. We used the Newcastle-Ottawa Scale to assess data quality. Data were pooled using DerSimonian and Laird random-effects models. We performed a meta-analysis of 18 adult studies for 28-day or 30-day hospital readmission; 7 adult studies of 30-day ED revisits and 5 paediatric studies of 72-hour or 7-day ED revisits. We also conducted a stratified analysis by whether access to interpretation services was verified/provided for the adult readmission analysis. MAIN OUTCOMES AND MEASURES: Odds of hospital readmissions within a 28-day or 30-day period and ED revisits within a 7-day period. RESULTS: We generated 4830 citations from all data sources, of which 49 (12 paediatric; 36 adult; 1 with both adult and paediatric) were included. In our meta-analysis, language discordant adult patients had increased odds of hospital readmissions (OR 1.11, 95% CI 1.04 to 1.18). Among the 4 studies that verified interpretation services for language discordant patient-clinician interactions, there was no difference in readmission (OR 0.90, 95% CI 0.77 to 1.05), while studies that did not specify interpretation service access/use found higher odds of readmission (OR 1.14, 95% CI 1.06 to 1.22). Adult patients with a non-dominant language preference had higher odds of ED revisits (OR 1.07, 95% CI 1.004 to 1.152) compared with adults with a dominant language preference. In 5 paediatric studies, children of parents language discordant with providers had higher odds of ED revisits at 72 hours (OR 1.12, 95% CI 1.05 to 1.19) and 7 days (OR 1.02, 95% CI 1.01 to 1.03) compared with patients whose parents had language concordant communications. DISCUSSION: Adult patients with a non-dominant language preference have more hospital readmissions and ED revisits, and children with parents who have a non-dominant language preference have more ED revisits. Providing interpretation services may mitigate the impact of language discordance and reduce hospital readmissions among adult patients. PROSPERO REGISTRATION NUMBER: CRD42022302871.

Quality of life measures and cost analysis of biologic versus synthetic mesh for ventral hernia repair: The Preventing Recurrence in Clean and Contaminated Hernias randomized clinical trial.

BACKGROUND: Although the most durable method for ventral hernia repairs involves using mesh, whether to use biologic mesh versus synthetic mesh remains controversial. This study aimed to compare synthetic and biologic meshes with respect to patient-reported quality of life scores and costs after ventral hernia repair surgeries. METHODS: This study is part of the Preventing Recurrence in Clean and Contaminated Hernias (PRICE) pragmatic randomized control trial conducted from March 2014 through October 2018. Patients were randomized 1:1 to undergo ventral hernia repair using either a biologic or synthetic mesh. The coprimary outcomes were 2-year changes in Visual Analog Scale, Activities Assessment Scale, Hernia-Related Quality-of-Life Survey, and Short-Form 36 Health Survey (SF-36) quality-of-life scores from repair. The secondary outcome was the overall cost per patient. RESULTS: Among the 165 patients included in the study, 82 were randomized to biologic meshes and 83 to synthetic meshes. There were no significant differences in the performance between the 2 mesh types with regard to quality-of-life measures using a mixed model approach. This result was consistent even when performing subgroup analysis based on wound contamination. However, nonparametric tests comparing the differences in quality-of-life measures from preoperative to 24-month postoperative timepoints revealed that the synthetic mesh group showed a greater reduction in disability than biologic mesh for the SF-36 (median [interquartile range] of 20 [5-30] vs 6 [1-20], P = .025). This difference was due to reductions in the physical role limitations (62 [0-100] vs 0 [0-50], P = .018) and the pain (38 [12-50] vs 12 [0-25], P = .012) domains of the SF-36. Overall cost per patient was greater for biologic meshes (mean [95% confidence interval] of $80,420 [$66,485-$94,355] vs $61,036 [$48,946-$73,125], P = .038), regardless of insurance type. CONCLUSION: In this randomized clinical trial, there were no differences in changes in quality-of-life scores at the 2-year timepoint except for the SF-36, where the synthetic mesh may be associated with less pain and physical role limitations than the biologic mesh. Overall costs per patient were less for synthetic than biologic mesh.

Atopic Dermatitis and Cardiovascular Risk in Pediatric Patients: A Systematic Review and Meta-Analysis.

Cardiovascular guidelines recommend early screening and preventative treatment for children with chronic inflammatory diseases. Atopic dermatitis (AD) is associated with cardiovascular risk in adults, but data in children are limited. We systematically searched for studies that examined the association between childhood AD and cardiovascular risk factors and outcomes. Data from 10 publications, including 577,148 individuals, revealed an association between AD and ischemic heart disease (n = 3, OR = 1.68, 95% confidence interval [CI] = 1.29-2.19) and diabetes (n = 4, OR = 1.31, 95% CI = 1.12-1.53), but this did not persist among studies that adjusted for potential confounders (n = 2, OR = 0.98, 95% CI = 0.35-2.75). Similarly, there was an association with lipid disorders but not across the entire population distribution (n = 7, OR = 1.24, 95% CI = 1.13-1.36, 95% prediction interval = 0.95-1.61). AD was not associated with hypertension (n = 5, OR = 1.15, 95% CI = 0.98-1.34, 95% prediction interval = 0.81-1.62) or stroke (n = 2, OR = 1.24, 95% CI = 0.94-1.62). Studies lacked detail on AD severity and important confounders such as body mass index, and the certainty of evidence was very low to low on the basis of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) assessments. Currently, data do not support a clinically meaningful increase in cardiovascular risk for children with AD.

Cytokine responses to SARS-COV2 infection in mother-infant dyads: a systematic review and meta-analysis.

Background: The COVID-19 pandemic has affected a significant number of pregnant women worldwide, but studies on immune responses have presented conflicting results. This study aims to systematically review cytokine profiles in pregnant women with SARS-CoV-2 infection and their infants to evaluate immune responses and potential transplacental transfer of cytokines. Materials and methods: A comprehensive search of 4 databases was conducted to identify relevant studies. Inclusion criteria included studies measuring individual cytokines in pregnant women and/or their neonates. Studies were evaluated for quality, and data were extracted for analysis. Meta-analyses were performed using the random-effects model. Results: Seventeen studies met the inclusion criteria, including data from 748 pregnant women and 287 infants. More than three of these studies evaluated data of 20 cytokines in maternal serum, and data of 10 cytokines was available from cord blood samples. Only the serum level of CXCL10 was significantly up-regulated in SARS-CoV-2 positive pregnant women (n = 339) compared to SARS-CoV-2 negative pregnant women (n = 409). Subset analysis of maternal samples (n = 183) collected during the acute phase of COVID-19 infection showed elevated CXCL10 and IFN-γ. No significant differences in cytokine levels were found between cord blood samples collected from infants born to mothers with (n = 97) and without (n = 190) COVID-19 during gestation. Subset analysis of cord blood samples collected during the acute phase of maternal infection was limited by insufficient data. The heterogeneity among the studies was substantial. Conclusion: The findings suggest that maternal cytokines responses to SARS-CoV-2 infection during pregnancy are not significantly dysregulated, except for CXCL10 and IFN-γ during the acute phase of illness. No evidence of increased cytokine levels in cord blood samples was observed, although this could be impacted by the time period between initial maternal infection and cord blood collection. These results provide some reassurance to parents and healthcare providers but should be interpreted cautiously due to study variations and limitations.

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

Revisiting the utility of prenatal ultrasound in the routine workup of first febrile UTI: A systematic review and meta-analysis of the negative predictive value of prenatal ultrasound for identification of urinary tract abnormalities after first febrile urinary tract infection in children.

CONTEXT: The current EAU/ESPU and recently retired AAP pediatric UTI guidelines recommend renal bladder ultrasound after first febrile UTI in children to screen for structural abnormalities, regardless of findings on prenatal ultrasound. OBJECTIVE: Test the hypothesis that a normal prenatal ultrasound could rule out urinary tract abnormality on post-UTI ultrasound. DATA SOURCES: Medline, Embase, Cochrane Library. STUDY SELECTION: Studies including pediatric patients with first febrile UTI who had both prenatal and post-UTI ultrasound. DATA EXTRACTION: Anatomical abnormalities detected by prenatal and post-UTI ultrasound as reported per individual study criteria were extracted. Meta-analyses of 9 studies (2981 patients) were performed using a random-effects model and composite estimates of the negative predictive value (NPV) of prenatal ultrasound were calculated. RESULTS: Overall summary NPV of prenatal ultrasound for all pediatric patients was 77%, with heterogeneity score (I2) 97.9%. Summary NPV of prenatal ultrasound for all patients under two years of age was similar at 75%, with I2 98.2% For the 4 studies to which we could apply a more stringent definition of abnormality, summary NPV was 85% and I2 97.5% for prediction of moderate post-UTI ultrasound abnormalities and summary NPV was 93% and I2 90.4% for severe abnormalities. DISCUSSION: While we calculated an 85% NPV for a normal prenatal ultrasound to rule out significant postnatal abnormality as defined within individual studies, substantial heterogeneity amongst publications limited the precision of our estimates. This highlights the need for more rigorous investigations with attention to timing of ultrasound and the application of clinically meaningful definitions for abnormal prenatal and post-UTI studies. This may allow judicious use of prenatal ultrasound to guide clinical management for children with first febrile UTI and minimize redundant imaging with potential for false positive results. Until then, the current guidelines are justified based on the limited and heterogenous data from the currently available published studies.

Racial Disparities in Emergency Department Physical Restraint Use: A Systematic Review and Meta-Analysis.

Importance: Recent studies have demonstrated that people of color are more likely to be restrained in emergency department (ED) settings compared with other patients, but many of these studies are based at a single site or health care system, limiting their generalizability. Objective: To synthesize existing literature on risk of physical restraint use in adult EDs, specifically in reference to patients of different racial and ethnic backgrounds. Data Sources: A systematic search of PubMed, Embase, Web of Science, and CINAHL was performed from database inception to February 8, 2022. Study Selection: Included peer-reviewed studies met 3 criteria: (1) published in English, (2) original human participants research performed in an adult ED, and (3) reported an outcome of physical restraint use by patient race or ethnicity. Studies were excluded if they were conducted outside of the US, or if full text was unavailable. Data Extraction and Synthesis: Four independent reviewers (V.E., M.M., D.D., and A.H.) abstracted data from selected articles following Meta-Analysis of Observational Studies in Epidemiology guidelines. A modified Newcastle-Ottawa scale was used to assess quality. A meta-analysis of restraint outcomes among minoritized racial and ethnic groups was performed using a random-effects model in 2022. Main Outcome(s) and Measure(s): Risk of physical restraint use in adult ED patients by racial and ethnic background. Results: The search yielded 1597 articles, of which 10 met inclusion criteria (0.63%). These studies represented 2 557 983 patient encounters and 24 030 events of physical restraint (0.94%). In the meta-analysis, Black patients were more likely to be restrained compared with White patients (RR, 1.31; 95% CI, 1.19-1.43) and to all non-Black patients (RR, 1.27; 95% CI, 1.23-1.31). With respect to ethnicity, Hispanic patients were less likely to be restrained compared with non-Hispanic patients (RR, 0.85; 95% CI, 0.81-0.89). Conclusions and Relevance: Physical restraint was uncommon, occurring in less than 1% of encounters, but adult Black patients experienced a significantly higher risk of physical restraint in ED settings compared with other racial groups. Hispanic patients were less likely to be restrained compared with non-Hispanic patients, though this observation may have occurred if Black patients, with a higher risk of restraint, were included in the non-Hispanic group. Further work, including qualitative studies, to explore and address mechanisms of racism at the interpersonal, institutional, and structural levels are needed.