Visual assessments of 11C-Pittsburgh compound-B PET vs. 18F-flutemetamol PET across the age spectrum.

OBJECTIVE: Visual assessments of amyloid-ß PET, used for Alzheimer's disease (AD) diagnosis and treatment evaluation, require a careful approach when different PET ligands are utilized. Because the gray matter (GM) and white matter (WM) ligand bindings vary with age, the objective was to investigate the agreement between visual reads of 11C- and 18F-PET scans. METHODS: Cognitively unimpaired (CU) younger adults (N = 30; 39.5 ± 6.0 years), CU older adults (N = 30; 68.6 ± 5.9 years), and adults with AD (N = 22; 67.0 ± 8.5 years) underwent brain MRI, 11C-Pittsburgh compound-B (PiB)-PET, and 18F-flutemetamol-PET. Amyloid-ß deposition was assessed visually by two nuclear medicine specialists on 11C-PiB-PET and 18F-flutemetamol-PET, and quantitatively by PET centiloids. RESULTS: Seventy-two 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant. However, 1 18F-flutemetamol-PET and 9 11C-PiB-PET were discordant with quantitative values. In four additional cases, while 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant, both were discordant with quantitative values. Disagreements in CU younger adults were only with 11C-PiB-PET visual reads. The remaining disagreements were with CU older adults. CONCLUSION: Age, GM/WM binding, amyloid-ß load, and disease severity may affect visual assessments of PET ligands. Increase in WM binding with age causes a loss of contrast between GM and WM on 11C-PiB-PET, particularly in CU younger adults, leading to false positivity. In CU older adults, increased WM signal may bleed more into cortical regions, hiding subtle cortical uptake, especially with 18F-flutemetamol, whereas 11C-PiB can detect true regional positivity. Understanding these differences will improve patient care and treatment evaluation in clinic and clinical trials.

Colocation of COVID-19 Vaccination Services at Syringe Service Programs for People Who Inject Drugs and People Experiencing Houselessness in Oregon.

OBJECTIVES: Integrating vaccination services with other essential health services could increase vaccination rates among socially marginalized populations. We examined the associations between colocation of vaccines at syringe service programs and COVID-19 vaccination status among people who inject drugs and people experiencing houselessness. METHODS: This study included 1891 participants aged ≥18 years at 9 sites in Oregon from July 2021 through March 2022. Participants self-reported whether they had ever received ≥1 dose of a COVID-19 vaccine. We calculated site-level COVID-19 vaccine availability and overall vaccination rates. We compared site-level vaccination rates and analyzed the association between vaccine availability and vaccination status. RESULTS: We found no significant difference in vaccination rates between sites that did and did not offer COVID-19 vaccines (t7 = -0.33; P = .75). We also found no significant association between vaccine availability and vaccination status. However, the odds of having received a COVID-19 vaccine were 2.79 times higher for each additional site visit during which COVID-19 vaccines were available (odds ratio [OR] = 2.79; 95% CI, 2.18-3.58; P < .001). The association between vaccine availability and vaccine status was not moderated by participant age (OR = 1.03; 95% CI, 0.99-1.07; P = .13) or housing instability (OR = 0.59; 95% CI, 0.13-2.60; P = .48). CONCLUSIONS: Colocating COVID-19 vaccines at syringe service programs was only positively associated with vaccination status if vaccines were offered frequently on-site. Future work should examine whether the frequency of offering vaccination services increases willingness to engage in vaccination and examine trust and convenience as potential mechanisms.

Baseline multimodal imaging to predict longitudinal clinical decline in atypical Alzheimer's disease.

There are recognized neuroimaging regions of interest in typical Alzheimer's disease which have been used to track disease progression and aid prognostication. However, there is a need for validated baseline imaging markers to predict clinical decline in atypical Alzheimer's Disease. We aimed to address this need by producing models from baseline imaging features using penalized regression and evaluating their predictive performance on various clinical measures. Baseline multimodal imaging data, in combination with clinical testing data at two time points from 46 atypical Alzheimer's Disease patients with a diagnosis of logopenic progressive aphasia (N = 24) or posterior cortical atrophy (N = 22), were used to generate our models. An additional 15 patients (logopenic progressive aphasia = 7, posterior cortical atrophy = 8), whose data were not used in our original analysis, were used to test our models. Patients underwent MRI, FDG-PET and Tau-PET imaging and a full neurologic battery at two time points. The Schaefer functional atlas was used to extract network-based and regional gray matter volume or PET SUVR values from baseline imaging. Penalized regression (Elastic Net) was used to create models to predict scores on testing at Time 2 while controlling for baseline performance, education, age, and sex. In addition, we created models using clinical or Meta Region of Interested (ROI) data to serve as comparisons. We found the degree of baseline involvement on neuroimaging was predictive of future performance on cognitive testing while controlling for the above measures on all three imaging modalities. In many cases, model predictability improved with the addition of network-based neuroimaging data to clinical data. We also found our network-based models performed superiorly to the comparison models comprised of only clinical or a Meta ROI score. Creating predictive models from imaging studies at a baseline time point that are agnostic to clinical diagnosis as we have described could prove invaluable in both the clinical and research setting, particularly in the development and implementation of future disease modifying therapies.

Functional Investigations of p53 Acetylation Enabled by Heterobifunctional Molecules.

Post-translational modifications (PTMs) dynamically regulate the critical stress response and tumor suppressive functions of p53. Among these, acetylation events mediated by multiple acetyltransferases lead to differential target gene activation and subsequent cell fate. However, our understanding of these events is incomplete due to, in part, the inability to selectively and dynamically control p53 acetylation. We recently developed a heterobifunctional small molecule system, AceTAG, to direct the acetyltransferase p300/CBP for targeted protein acetylation in cells. Here, we expand AceTAG to leverage the acetyltransferase PCAF/GCN5 and apply these tools to investigate the functional consequences of targeted p53 acetylation in human cancer cells. We demonstrate that the recruitment of p300/CBP or PCAF/GCN5 to p53 results in distinct acetylation events and differentiated transcriptional activities. Further, we show that chemically induced acetylation of multiple hotspot p53 mutants results in increased stabilization and enhancement of transcriptional activity. Collectively, these studies demonstrate the utility of AceTAG for functional investigations of protein acetylation.

Overview of ADNI MRI.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

Approach Bias and Tobacco Craving as Mechanisms of the Effect of Approach Bias Retraining on Smoking Cessation.

INTRODUCTION: Approach bias, the automatic tendency to advance toward, rather than move away from appetitive cues, has been associated with greater tobacco cravings, dependence, and likelihood of smoking relapse. Approach bias retraining (ABR) has emerged as one way to reduce approach bias and promote avoidance toward smoking cues. Yet, additional research is needed to identify the mechanisms that may help explain the effect of ABR on smoking cessation. METHODS: The current study uses data collected as part of a randomized controlled trial to test two unique mechanisms of action ([1] approach bias and [2] tobacco craving) for the efficacy of standard smoking cessation treatment (ST) augmented by ABR on smoking abstinence. Participants were 96 adult daily smokers (Mage=43.1, SD=10.7) motivated to quit smoking. RESULTS: Results showed that lower approach bias and lower cravings at a treatment session were significantly related to next session smoking abstinence (p's<.018). Further, deviations in approach bias partially mediated the effect of ABR on smoking abstinence (ab=-12.17, 95%CI: [-29.67, -0.53]). However, deviations in tobacco craving did not mediate this relation (ab=.40, 95%CI: [-.27, 1.34]). CONCLUSIONS: The current findings add to extant literature by identifying approach bias as a mechanism of action of the effect of ABR on smoking abstinence during smoking cessation treatment. IMPLICATIONS: The current study adds to our knowledge on the effectiveness of approach bias retraining (ABR) as a part of smoking cessation treatment. Results indicate that reductions in approach bias partially mediate the effect of ABR on smoking abstinence. These findings are consistent with previous research on alcohol-dependent adults and underline the potential of ABR to reduce approach bias and promote smoking cessation among smokers. Such findings could inform the development of future research exploring more targeted and effective smoking cessation interventions, ultimately improving outcomes for individuals attempting to quit smoking.

Impact of upgrading from a 25-cm to a 30-cm z-axis field of view digital PET/CT in a pediatric hospital.

BACKGROUND: Increased positron emission tomography (PET) scanner z-axis coverage provides an opportunity in pediatrics to reduce dose, anesthesia, or repeat scans due to motion. OBJECTIVE: Recently, our digital PET scanner was upgraded from a 25-cm to a 30-cm z-axis coverage. We compare the two systems through National Electrical Manufacturing Association (NEMA) testing and evaluation of paired images from patients scanned on both systems. MATERIALS AND METHODS: NEMA testing and a retrospective review of pediatric patients who underwent clinically indicated 18F-fluorodeoxyglucose (FDG) PET computed tomography (PET/CT) on both systems with unchanged acquisition parameters were performed. Image quality was assessed with liver signal to noise ratio (SNR-liver) and contrast to noise ratio (CNR) in the thigh muscle and liver with results compared with an unpaired t-test. Three readers independently reviewed paired (25 cm and 30 cm) images from the same patient, blinded to scanner configuration. RESULTS: Expansion to 30 cm increased system sensitivity to 29.8% (23.4 cps/kBq to 30.4 cps/kBq). Seventeen patients (6 male/11 female, median age 12.5 (IQR 8.3-15.0) years, median weight 53.7 (IQR 34.2-68.7) kg) were included. SNR-liver and CNR increased by 35.1% (IQR 19.0-48.4%) and 43.1% (IQR 6.2-50.2%) (P-value <0.001), respectively. All readers preferred images from the 30-cm configuration. A median of 1 (IQR 1-1) for fewer bed positions was required with the 30-cm configuration allowing a median of 91 (IQR 47-136) s for shorter scans. CONCLUSION: Increasing z-axis coverage from 25 to 30 cm on a current-generation digital PET scanner significantly improved PET system performance and patient image quality, and reduced scan duration.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). ß-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac ß-adrenoceptors (ßARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local ßAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different ßAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by ß1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced ß1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the ß1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with ß1AR were observed. Stimulating ß1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament ß1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

In-Home Remote Assessment of the MDS-UPDRS Part III: Multi-Cultural Development and Validation of a Guide for Patients.

BACKGROUND: The shift toward virtualized care introduces challenges in assessing the motor severity of Parkinson's disease (PD). The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, the most used rating scale in PD, lacks validation for synchronous remote administration. OBJECTIVE: Our goal was to validate the usability of a patient guide to allow an accurate video-based MDS-UDPRS part III remote examination. METHODS: We conducted a multi-stage mixed methods study that included a team consensus for the concept of the guide, cognitive pretesting, and usability (system usability scale, [SUS]) testing in five sites (total n = 25 participants) with distinct linguistic and cultural contexts. RESULTS: A multi-language (English, Portuguese, Spanish, and traditional Chinese) largely pictograph guide of the MDS-UPDRS part III remote examination reached benchmark for usability (SUS score ≥68) in 25 participants who completed the synchronous remote assessment. CONCLUSIONS: The MDS-UDPRS part III remote examination guide can be used remotely accurately, and facilitate clinical practice and research in a paradigm of telemedicine.

American Football Headgear Impairs Visuomotor Drill Performance in Division I NCAA Football Athletes.

Background/Objectives: Previous evidence has shown that American football headgear (e.g., facemasks, visors/eye shields) differentially impairs reaction time (RT) to visual stimuli, most notably in peripheral fields of view. However, this has only been established with stationary RT testing, which may not translate to gameplay situations that require gross motor skills. Therefore, the purpose of this study was to build upon previous findings to elucidate the effects of various American football headgear on gross motor visuomotor drill performance. Methods: Division 1 NCAA football players (n = 16) with normal/corrected-to-normal vision participated and completed two experiments (EXP), each with differing conditions: EXP1- Varying facemask reinforcement and EXP2- Varying visor/eye shield light transmittance. In EXP1, participants completed an agility test for the following conditions: baseline/no helmet (BL), helmet + light (HL), helmet + medium (HM), and helmet + heavy (HH) face mask reinforcement. In EXP2, participants completed an agility test for the following conditions: baseline/no helmet (BL), helmet + clear visor (HCV), helmet + smoke-tinted visor (HSV), and helmet + mirrored visor (HMV). For each condition in EXP1 and EXP2, participants completed a reactive agility task using a FITLIGHT trainer system where five poles were equipped with a total of ten LED sensors and were placed in a semi-circle 1 m around a center point. Participants were asked to step and reach with their hands to hit each ten lights individually as fast as possible upon illumination. Each reactive agility test was repeated for a total of three attempts. Results: Average reaction time was analyzed and compared between conditions and according to visual fields of interest (e.g., central vs. peripheral). Results from EXP1 showed that compared to BL, reactive agility was worsened by HL (p = 0.030), HM (p = 0.034), and HH (p = 0.003) conditions. No differences between facemask conditions existed for overall performance (p > 0.05). For EXP2, HCV (p < 0.001), HSV (p < 0.001), and HMV (p < 0.001) conditions resulted in worsened reactive agility performance compared to BL. No differences between visor conditions existed for overall performance (p > 0.05). Conclusions: Overall, these findings suggest that American football headgear impairs reactive agility, which could result in worsened game performance and safety. Future studies investigating training strategies to overcome impairments are warranted.

The Battle of Endoscopic Bariatric Therapies for Obesity: Endoscopic Sleeve Gastroplasty Versus Endoscopically Inserted Intragastric Balloon-A Pairwise Meta-Analysis of Comparative Studies and a Call for Randomized Controlled Trials.

BACKGROUND: Endoscopic sleeve gastroplasty (ESG) represents the latest primary endoscopic intervention for managing obesity. Both ESG and intragastric balloons (IGBs) have demonstrated effectiveness and safety for weight loss. However, there is a paucity of high-quality evidence supporting the superiority of one over the other, and no pairwise meta-analysis of comparative studies has been published to date. Our aim was to conduct a pairwise meta-analysis of comparative studies directly comparing ESG and IGB. METHODS: We systematically conducted a literature search on PubMed and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our search used specific search terms. The Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) Tool was used to evaluate the quality of the included studies. Data were analyzed using Review Manager (RevMan) 5.4.1 software with a random-effects model. The statistical method used was the Mantel-Haenszel method. For dichotomous data, the effect size was represented using odds ratio (OR), while mean difference (MD) was utilized as the effect size for continuous data. RESULTS: After screening 967 records, a total of 9 studies met the inclusion criteria for this meta-analysis (5302 patients). The quality assessment categorized 5 studies as having a moderate risk of bias, while 3 studies were classified as having a low risk of bias. Sufficient information was not available for one study to ascertain its overall quality. A statistically significant increase in total weight loss percentage (TWL%) at 1 and 6 months was observed with ESG compared with IGB. In addition, a statistically insignificant decrease in the incidence of adverse events and readmissions was observed with ESG. Furthermore, a statistically significant decrease in the incidence of reintervention was observed with ESG. CONCLUSIONS: While this study suggests a higher TWL% associated with ESG compared with IGB, drawing definitive conclusions is challenging due to limitations identified during a comprehensive quality assessment of the available literature. We advocate for randomized controlled trials (RCTs) directly comparing the newer IGB (with a 12-mo placement duration) with ESG. However, this study consistently reveals higher rates of early reintervention (re-endoscopy) within the IGB group, primarily necessitated by the removal or adjustment of the IGB due to intolerance. Given the additional intervention required at 6 or 12 months to remove the temporarily placed IGB, this trend may imply that IGB is less economically viable than ESG. Cost-effectiveness analyses comparing ESG and IGB are warranted to provide valuable scientific insights.

Evaluating scholastic achievement in pediatric brain tumor survivors compared to healthy controls.

BACKGROUND: Radiotherapy (RT) causes cognitive deficits in pediatric brain tumor survivors (PBTS). Traditionally, this is measured using neuropsychological testing, which lack pre-diagnosis baseline and do not necessarily trigger action. This pilot project investigated a novel patient-centered outcome of scholastic performance using state-collected educational data. METHODS: We retrospectively analyzed scholastic achievements in children residing in Florida. Eligibility in the treatment group received brain-directed RT between 2007 - 2020 at our institution. Controls were matched at a 3:1 ratio by age, grade, district, and free or reduced lunch (FRL) eligibility. The Florida Department of Education provided educational records for both groups. Generalized linear mixed-effects models were used to predict scholastic outcomes with covariates age, time (binary value of pre- or post-RT), treatment group, and the primary independent variable as the interaction term between time and treatment. Scholastic data was matched with institutional clinical data. RESULTS: Fifty PBTS and 150 matched controls were included for analysis. Median age of PBTS was 12, 12% identified as Black, and 18% as Hispanic. Fifty-two percent were FRL eligible. Forty percent received craniospinal irradiation, and 56% received chemotherapy. Post-RT PBTS had 21 times the odds of receiving accommodations (p=0.006), twice the odds of being retained (p=0.010), and 42% lower odds than controls receiving a passing mathematics score (p=0.068). CONCLUSIONS: To our knowledge, this is the first American experience to successfully link individual scholastic and clinical data. Scholastic performance serves as a meaningful patient-centered outcome complementing the existing suite of neuropsychological testing.

Organic two-photon-absorbing photosensitizers can overcome competing light absorption in organic photocatalysis.

Conventional organic photocatalysis typically relies on ultraviolet and short-wavelength visible photons as the energy source. However, this approach often suffers from competing light absorption by reactants, products, intermediates, and co-catalysts, leading to reduced quantum efficiency and side reactions. To address this issue, we developed novel organic two-photon-absorbing (TPA) photosensitizers capable of functioning under deep red and near-infrared light irradiation. Three model reactions including cyclization, Sonogashira Csp2-Csp cross-coupling, and Csp2-N cross-coupling reactions were selected to compare the performance of the new photosensitizers under both blue (427 nm) and deep red (660 nm) light irradiation. The obtained results unambiguously prove that for reactions involving blue light-absorbing reactants, products, and/or co-catalysts, deep red light source resulted in better performance than blue light when utilizing our TPA photosensitizers. This work highlights the potential of our metal-free TPA photosensitizers as a sustainable and effective solution to mitigate the competing light absorption issue in photocatalysis, not only expanding the scope of organic photocatalysts but also reducing reliance on expensive Ru/Ir/Os-based photosensitizers.

5-Year Outcomes of Anterior Mitral Leaflet Laceration to Prevent Outflow Obstruction.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a common, often fatal complication of transcatheter mitral valve replacement (TMVR). Laceration of the anterior mitral leaflet to prevent outflow obstruction (LAMPOON) was safe and effective at preventing LVOT obstruction at 30 days in the National Heart, Lung, and Blood Institute LAMPOON trial. OBJECTIVES: The authors report the 5-year trial outcomes. METHODS: The National Heart, Lung, and Blood Institute LAMPOON trial was a prospective, multicenter, single-arm safety and feasibility study of LAMPOON and transseptal SAPIEN 3 TMVR in annuloplasty rings (valve-in-ring) or native mitral annular calcification (MAC) (valve-in-MAC). All subjects had high predicted risk for LVOT obstruction. Subjects were not excluded for excessive frailty or comorbidity. The primary endpoints were technical success and safety at 30 days. Secondary clinical and echocardiographic endpoints were assessed at 1 year and clinical follow-up at 5 years. RESULTS: Thirty subjects were enrolled between June 2017 and June 2018, equally between the valve-in-MAC and valve-in-ring arms. At 30 days, LAMPOON was successful in all 30 subjects, with no strokes, 1 (3%) death, and 1 (3%) moderate LVOT obstruction. Eighteen (65%) survived to 1 year, and 7 (25%) survived to 5 years. Six (20%) were hospitalized for heart failure in the first year. From baseline to 1 year, there was a 24-point improvement in Kansas City Cardiomyopathy Questionnaire score and a 60-m improvement in 6-minute walk distance. There was no significant change in N-terminal pro-brain natriuretic peptide. At 1 year, LVOT gradients remained low. CONCLUSIONS: LAMPOON enabled TMVR despite the risk for LVOT obstruction. There were no long-term complications associated with LAMPOON. The selection of inoperable patients limited assessment of long-term survival following TMVR. (NHLBI DIR LAMPOON Study: Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation; NCT03015194).

Varying optimal power for height-standardisation of childhood weight, fat mass and fat-free mass across the obesity epidemic.

INTRODUCTION: Childhood adiposity markers can be standardised for height in the form of indices (marker/heightp) to make meaningful comparisons of adiposity patterns within and between individuals of differing heights. The optimal value of p has been shown to differ by birth year, sex, age, and ethnicity. We investigated whether height powers for childhood weight and fat mass (FM) differed by birth year, sex, or age over the period before and during the child obesity epidemic in Copenhagen. SETTING/METHODS: Population-based cross-sectional study of 391,801 schoolchildren aged 7 years, 10 years and 13 years, born between 1930 and 1996, from the Copenhagen School Health Records Register. Sex- and age-specific estimates of the height powers for weight and FM were obtained using log-log regression, stratified by a decade of birth. RESULTS: For weight, amongst children born 1930-39, optimal height powers at 7 years were 2.20 (95% CI: 2.19-2.22) for boys and 2.28 (95% CI: 2.26-2.30) for girls. These increased with birth year to 2.82 (95% CI: 2.76-2.87) and 2.92 (95% CI: 2.87-2.97) for boys and girls born in 1990-96, respectively. For FM, amongst those born 1930-39, powers at 7 years were 2.46 (95% CI: 2.42-2.51) and 2.58 (95% CI: 2.53-2.63) for boys and girls, respectively, and increased with birth year reaching 3.89 (95% CI: 3.75-4.02) and 3.93 (95% CI: 3.80-4.06) for boys and girls born 1990-96, respectively. Powers within birth cohort groups for weight and FM were higher at 10 years than at 7 years, though similar increases across groups were observed at both ages. At 13 years, height powers for weight and FM initially increased with the birth year before declining from the 1970s/80s. CONCLUSION: Due to increases in the standard deviation of weight and FM during the obesity epidemic, optimal height powers needed to standardise childhood weight and FM varied by birth year, sex, and age. Adiposity indices using a uniform height power mean different things for different birth cohort groups, sexes, and ages thus should be interpreted with caution. Alternative methods to account for height in epidemiological analyses are needed.

Engineering error correcting dynamics in nanomechanical systems.

Nanomechanical oscillators are an alternative platform for computation in harsh environments. However, external perturbations arising from such environments may hinder information processing by introducing errors into the computing system. Here, we simulate the dynamics of three coupled Duffing oscillators whose multiple equilibrium states can be used for information processing and storage. Our analysis reveals that, within experimentally relevant parameters, error correcting dynamics can emerge, wherein the system's state is robust against random external impulses. We find that oscillators in this configuration have several surprising and attractive features, including dynamic isolation of resonators exposed to extreme impulses and the ability to correct simultaneous errors.

Negative self-referent cognition predicts future depression symptom change: an intensive sampling approach.

Cognitive theories of depression assert that negative self-referent cognition has a causal role in the development and maintenance of depression symptoms, but few studies have examined temporal associations between these constructs using intensive, longitudinal sampling strategies. In three samples of undergraduate students, we examined associations between change in self-referent processing and depression across 5 daily assessments (Sample 1, N = 303, 1,194 measurements, 79% adherence), 7 daily assessments (Sample 2, N = 313, 1,784 measurements, 81% adherence), and 7 weekly assessments (Sample 3; N = 155, 833 measurements, 81% adherence). Random intercept cross-lagged panel models indicated large cross-lagged effects in two of the three samples (Samples 1 and 3 but not Sample 2), such that more negative self-referent thinking than usual was significantly associated with a subsequent increase in depression symptoms at the next time lag. Notably, change in depression from usual was not associated with increases in negative self-referent processing at the next time point in any sample. These findings suggest that change in negative self-referent processing may be causally linked to future increases in depression on a day-to-day and week-to-week basis, although confidence in this conclusion is tempered somewhat by a lack of replication in Sample 2.

Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists.

Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities.

Charting the Dynamic Trophoblast Plasma Membrane Identifies LYN As a Functional Regulator of Syncytialization.

The differentiation of placental cytotrophoblasts (CTBs) into the syncytiotrophoblast (STB) layer results in a significant remodeling of the plasma membrane proteome. Here, we use a peroxidase-catalyzed proximity labeling strategy to map the dynamic plasma membrane proteomes of CTBs and STBs. Coupled with mass-spectrometry-based proteomics, we identify hundreds of plasma membrane proteins and observe relative changes in protein abundance throughout differentiation, including the upregulation of the plasma-membrane-localized nonreceptor tyrosine kinase LYN. We show that both siRNA-mediated knockdown and small molecule inhibition of LYN kinase function impairs CTB fusion and reduces the expression of syncytialization markers, presenting a function for LYN outside of its canonical role in immunological signaling. Our results demonstrate the use of the proximity labeling platform to discover functional regulators within the plasma membrane and provide new avenues to regulate trophoblast differentiation.

MR enterography radiologic ulcers in newly diagnosed ileal Crohn disease in children: frequency, inter-radiologist agreement, and clinical correlation.

BACKGROUND: Radiologic ulcers are increasingly recognized as an imaging finding of bowel wall active inflammation in Crohn disease (CD). OBJECTIVE: To determine the frequency of ulcers at MR enterography (MRE) in children with newly diagnosed ileal CD, assess agreement between radiologists, and evaluate if their presence correlates with other imaging and clinical features of intestinal active inflammation. MATERIALS AND METHODS: This retrospective study included 108 consecutive pediatric patients (ages 6-18 years) with newly diagnosed ileal CD that underwent clinical MRE prior to treatment initiation between January 2021 and December 2022. MRE examinations were independently reviewed by three pediatric radiologists who indicated the presence vs. absence of ulcers, ulcer severity (categorical depth), and ulcer extent (categorical number of ulcers). Maximum bowel wall thickness and length of disease were measured and averaged across readers. Patient demographics and clinical inflammatory markers were documented from electronic health records. Inter-radiologist agreement was assessed using Fleiss' kappa (k) statistics. Student's t-test was used to compare continuous variables. RESULTS: Mean patient age was 13.9 years (67 [62%] boys). Radiologic ulcers were recorded in 64/108 (59.3%) cases by reader 1, 70/108 (64.8%) cases by reader 2, and 49/108 (45.4%) cases by reader 3 (k = 0.36). Based on majority consensus, radiologic ulcers were present in 60/108 (55.6%) participants. Inter-radiologist agreement for ulcer severity was k = 0.23, while ulcer extent was k = 0.66. There were significant differences in C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, albumin, maximum bowel wall thickness, and length of disease between patients without and with radiologic ulcers (P < 0.05). The sensitivity and specificity of MRE for detecting endoscopic ulcers were 66.7% (95% CI, 52.1-79.2%) and 69.2% (95% CI, 48.2-85.7%), respectively. CONCLUSION: Radiologic ulcers are visible in children with newly diagnosed ileal CD, although inter-radiologist agreement is only fair. The presence of ulcers is associated with clinical laboratory inflammatory markers as well as other MRE findings of disease activity and is an additional imaging finding that can be used to evaluate intestinal inflammation.