Mixed effect estimation in deep compartment models: Variational methods outperform first-order approximations.

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method.

Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

BACKGROUND: Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. STUDY DESIGN AND METHODS: This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. RESULTS: Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. DISCUSSION: This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

Much lower prevalence and mortality of chronic obstructive pulmonary disease in Japan than in the US despite higher smoking rates: A meta analysis/systematic review.

BACKGROUND: A recent systematic review showed Japan's mortality from chronic obstructive pulmonary disease (COPD) is the lowest among 204 countries, despite notably higher smoking rates in men in Japan than in the US. This study aims to compare (1) trends in smoking rates, (2) trends in COPD mortality, and (3) the spirometry-based COPD prevalence in the general adult population between Japan and the US. METHODS: Age- and sex-specific smoking rates from the 1980s through 2010s and COPD mortality from 1999 through 2019 were obtained from national surveys and official statistics (International Classification of Diseases-10th codes J40-44), respectively. A systematic review and meta-analysis was performed to estimate COPD prevalence in Japan, while the National Health and Nutrition Examination Survey 2007-2012 was used for the US. A fixed ratio of 0.7 of forced expiratory volume in the first second of forced vital capacity was used to define COPD. RESULTS: Over the past four decades, men in Japan consistently had 20-30% higher smoking rates than their US counterparts. From 1999-2019, age-adjusted COPD mortality in men in Japan was only a third of the US, whereas that in women was less than a tenth in 2019. Synthesizing data from 11 studies, involving 89,955 participants, Japan's COPD prevalence was more than 10% lower than in the US in almost all age groups for both sexes. CONCLUSIONS: This study showed markedly lower rates of COPD in Japan than in the US. Investigating factors contributing to the paradoxical observations could lead to advancing COPD risk reduction strategies.

New ion radii for oxides and oxysalts, fluorides, chlorides and nitrides.

Ion radii are derived here from the characteristic (grand mean) bond lengths for (i) 135 ions bonded to oxygen in 459 configurations (on the basis of coordination number) using 177 143 bond lengths extracted from 30 805 ordered coordination polyhedra from 9210 crystal structures; and (ii) 76 ions bonded to nitrogen in 137 configurations using 4048 bond lengths extracted from 875 ordered coordination polyhedra from 434 crystal structures. There are two broad categories of use for ion radii: (1) those methods which use the relative sizes of cation and anion radii to predict local atomic arrangements; (2) those methods which compare the radii of different cations (or the radii of different anions) to predict local atomic arrangements. There is much uncertainty with regard to the relative sizes of cations and anions, giving rise to the common failure of type (1) methods, e.g. Pauling's first rule which purports to relate the coordination adopted by cations to the radius ratio of the constituent cation and anion. Conversely, type (2) methods, which involve comparing the sizes of different cations with each other (or different anions with each other), can give very accurate predictions of site occupancies, physical properties etc. Methods belonging to type (2) can equally well use the characteristic bond lengths themselves (from which the radii are derived) in place of radii to develop correlations and predict crystal properties. Extensive quantum-mechanical calculations of electron density in crystals in the literature indicate that the radii of both cations and anions are quite variable with local arrangement, suggesting significant problems with any use of ion radii. However, the dichotomy between the experimentally derived ion radii and the quantum-mechanical calculations of electron density in crystals is removed by the recognition that ion radii are proxy variables for characteristic bond lengths in type (2) relations.

Clearing-enabled light sheet microscopy as a novel method for three-dimensional mapping of the sensory innervation of the mouse knee.

A major barrier that hampers our understanding of the precise anatomic distribution of pain sensing nerves in and around the joint is the limited view obtained from traditional two dimensional (D) histological approaches. Therefore, our objective was to develop a workflow that allows examination of the innervation of the intact mouse knee joint in 3D by employing clearing-enabled light sheet microscopy. We first surveyed existing clearing protocols (SUMIC, PEGASOS, and DISCO) to determine their ability to clear the whole mouse knee joint, and discovered that a DISCO protocol provided the most optimal transparency for light sheet microscopy imaging. We then modified the DISCO protocol to enhance binding and penetration of antibodies used for labeling nerves. Using the pan-neuronal PGP9.5 antibody, our protocol allowed 3D visualization of innervation in and around the mouse knee joint. We then implemented the workflow in mice intra-articularly injected with nerve growth factor (NGF) to determine whether changes in the nerve density can be observed. Both 3D and 2D analytical approaches of the light sheet microscopy images demonstrated quantifiable changes in midjoint nerve density following 4 weeks of NGF injection in the medial but not in the lateral joint compartment. We provide, for the first time, a comprehensive workflow that allows detailed and quantifiable examination of mouse knee joint innervation in 3D.

Associations between toxicity-weighted concentrations and dementia risk: Results from the Cardiovascular Health Cognition Study.

BACKGROUND: Air pollution is a modifiable risk factor for dementia. Yet, studies on specific sources of air pollution (i.e., toxic chemical emissions from industrial facilities) and dementia risk are scarce. We examined associations between toxicity-weighted concentrations of industrial pollution and dementia outcomes among a large, multi-site cohort of older adults. METHODS: Participants (n = 2770) were ≥ 65 years old (Mean = 75.3, SD = 5.1 years) from the Cardiovascular Health Cognition Study (1992-1999). Toxicity-weighted concentrations were estimated using the Risk Screening Environmental Indicator (RSEI) model which incorporates total reported chemical emissions with toxicity, fate, and transport models. Estimates were aggregated to participants' baseline census tract, averaged across 1988-1992, and log2-transformed. Dementia status was clinically adjudicated in 1998-1999 and categorized by subtype (Alzheimer's, vascular, mixed). We assessed whether RSEI-estimated toxicity-weighted concentrations were associated with 1) odds of prevalent dementia and 2) incident dementia risk by subtype. RESULTS: After adjusting for individual and census-tract level covariates, a doubling in toxicity-weighted concentrations was associated with 9 % higher odds of prevalent dementia (OR = 1.09, 95 % CI: 1.00, 1.19). In discrete-time survival models, each doubling in toxicity-weighted concentrations was associated with a 16 % greater hazard of vascular dementia (HR = 1.16, 95 % CI: 1.01, 1.34) but was not significantly associated with all-cause, Alzheimer's disease, or mixed dementia (p's > 0.05). DISCUSSION: Living in regions with higher toxicity-weighted concentrations was associated with higher odds of prevalent dementia and a higher risk of incident vascular dementia in this large, community-based cohort of older adults. These findings support the need for additional studies to examine whether toxic chemical emissions from industrial and federal facilities may be a modifiable target for dementia prevention.

Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate-Resistant Prostate Cancer.

Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T. SIGNIFICANCE: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.

The multifaceted role of c-di-AMP signaling in the regulation of Porphyromonas gingivalis lipopolysaccharide structure and function.

Background: This study unveils the intricate functional association between cyclic di-3',5'-adenylic acid (c-di-AMP) signaling, cellular bioenergetics, and the regulation of lipopolysaccharide (LPS) profile in Porphyromonas gingivalis, a Gram-negative obligate anaerobe considered as a keystone pathogen involved in the pathogenesis of chronic periodontitis. Previous research has identified variations in P. gingivalis LPS profile as a major virulence factor, yet the underlying mechanism of its modulation has remained elusive. Methods: We employed a comprehensive methodological approach, combining two mutants exhibiting varying levels of c-di-AMP compared to the wild type, alongside an optimized analytical methodology that combines conventional mass spectrometry techniques with a novel approach known as FLATn. Results: We demonstrate that c-di-AMP acts as a metabolic nexus, connecting bioenergetic status to nuanced shifts in fatty acid and glycosyl profiles within P. gingivalis LPS. Notably, the predicted regulator gene cdaR, serving as a potent regulator of c-di-AMP synthesis, was found essential for producing N-acetylgalactosamine and an unidentified glycolipid class associated with the LPS profile. Conclusion: The multifaceted roles of c-di-AMP in bacterial physiology are underscored, emphasizing its significance in orchestrating adaptive responses to stimuli. Furthermore, our findings illuminate the significance of LPS variations and c-di-AMP signaling in determining the biological activities and immunostimulatory potential of P. gingivalis LPS, promoting a pathoadaptive strategy. The study expands the understanding of c-di-AMP pathways in Gram-negative species, laying a foundation for future investigations into the mechanisms governing variations in LPS structure at the molecular level and their implications for host-pathogen interactions.

The Proposed 9th Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The 9th edition TNM classification of lung cancer, which is scheduled to take effect in January 2025, addresses this need. It is based on a large international database, multidisciplinary input, and extensive statistical analyses. Key features of the 9th edition include validation of the significant changes in the T component introduced in the 8th edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA, and IIIB. This article summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the 9th edition system.

Attachment security and disorganization in infants of mothers with severe psychiatric disorder: Exploring the role of comorbid personality disorder.

The aim of this preliminary study was to explore infant-mother attachment quality in a Dutch clinical sample of mothers with severe psychiatric disorder, with or without comorbid personality disorder. Thirty-two mothers were recruited through specialized secondary and tertiary outpatient clinics and mental health institutions. Maternal psychiatric and personality diagnoses were verified with structured clinical interviews during pregnancy. Maternal concurrent level of psychiatric symptoms was assessed by self-report and infant-mother attachment quality by observation in the Strange Situation Procedure at 14 months postpartum. In the full sample, almost half of the infants were classified as disorganized. All infants of mothers with a comorbid personality disorder were classified as either insecure or disorganized. Infants of mothers with a comorbid personality disorder had a significantly higher disorganization score than infants of mothers with a psychiatric disorder only. Continuous attachment security scores did not differ significantly between groups. In the full sample, continuous infant attachment security and disorganization score were not significantly correlated with the level of maternal concurrent psychiatric symptoms. Our exploratory findings suggest a specific link between maternal psychiatric and comorbid personality disorder and attachment disorganization. Moreover, chronicity of symptoms appears more relevant for attachment behaviors than the severity of concurrent psychiatric symptoms. Maternal personality disorder may have a strong formative impact on infant attachment security and disorganization, which warrants further research to inform clinical practice, in order to reduce the risk of intergenerational transmission of maternal psychopathology.

Oncogenic signaling in the adult Drosophila prostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation.

Drosophila models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages of Drosophila development, when tissues are highly mitotically active, or stem cells are abundant. Fewer Drosophila tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. The Drosophila accessory glands are prostate-like tissues and a model for some aspects of prostate tumorigenesis using this tissue has been explored. In this model, oncogenic signaling was induced during the proliferative stage of accessory gland development, raising the question of how oncogenic activity would impact the terminally differentiated and postmitotic adult tissue. Here, we show that oncogenic signaling in the adult Drosophila accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that observed in mitotic larval tissues, but in the absence of proliferation. Oncogenic signaling in the adult postmitotic gland leads to tissue hyperplasia with nuclear anaplasia and aneuploidy through endoreduplication, which increases polyploidy and occasionally results in non-mitotic neoplastic-like extrusions. We compare gene expression changes in our Drosophila model with that of endocycling prostate cancer cells induced by chemotherapy, which potentially mediate tumor recurrence after treatment. Similar signaling pathways are activated in the Drosophila gland and endocycling cancer cells, suggesting the adult accessory glands provide a useful model for aspects of prostate cancer progression that do not involve cellular proliferation.

Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α ). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index (ABI) metric, a transformation of α , and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α . Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical use in a large dataset.

Impact of Local and Nonlocal Vibronic Coupling on the Absorption and Emission Spectra of J- and H-Dimers.

The impact of exciton-vibrational (EV) coupling involving low-energy ("slow") intermolecular vibrations and higher-energy ("fast") intramolecular vibrations on the absorption and emission spectra of H- and J-dimers is studied theoretically for a pair of chromophores with excitonic coupling dominated by transition dipole-dipole coupling, JC. Exact quantum-mechanical solutions based on a Frenkel-Holstein-Peierls Hamiltonian reveal a fascinating interplay between the two coupling sources in determining the spectral line widths, Stoke shifts and radiative decay rates. It is shown that the ratio rules derived from the vibronic progression of the fast mode in molecular dimers remain valid under the influence of slow-mode EV coupling under most conditions. However, a highly unusual aggregate behavior occurs when the product of local and nonlocal couplings, |gLgNL|, exceeds 2ℏωs|JC|, where ℏωs is the energy of the slow mode. In this regime and when gL and gNL are in-phase, an H-dimer (JC > 0) becomes strongly emissive and can even be super-radiant, while a J-dimer (JC < 0) with out-of-phase gL and gNL values becomes subradiant. Such behaviors are in marked contrast to the predictions of Kasha theory and demonstrate the richness of the photophysical behavior resulting from EV coupling involving inter- and intramolecular vibrations.

P-Factor(s) for Youth Psychopathology Across Informants and Models in 24 Societies.

OBJECTIVE: Although the significance of the general factor of psychopathology (p) is being increasingly recognized, it remains unclear how to best operationalize and measure p. To test variations in the operationalizations of p and make practical recommendations for its assessment, we compared p-factor scores derived from four models. METHODS: We compared p scores derived from principal axis (Model 1), hierarchical factor (Model 2), and bifactor (Model 3) analyses, plus a Total Problem score (sum of unit-weighted ratings of all problem items; Model 4) for parent- and self-rated youth psychopathology from 24 societies. Separately for each sample, we fitted the models to parent-ratings on the Child Behavior Checklist for Ages 6-18 (CBCL/6-18) and self-ratings on the Youth Self-Report (YSR) for 25,643 11-18-year-olds. Separately for each sample, we computed correlations between p-scores obtained for each pair of models, cross-informant correlations between p-scores for each model, and Q-correlations between mean item x p-score correlations for each pair of models. RESULTS: Results were similar for all models, as indicated by correlations of .973-.994 between p-scores for Models 1-4, plus similar cross-informant correlations between CBCL/6-18 and YSR Model 1-4 p-scores. Item x p correlations had similar rank orders between Models 1-4, as indicated by Q correlations of .957-.993. CONCLUSIONS: The similar results obtained for Models 1-4 argue for using the simplest model - the unit-weighted Total Problem score - to measure p for clinical and research assessment of youth psychopathology. Practical methods for measuring p may advance the field toward transdiagnostic patterns of problems.

Violence and aggression against educators and school personnel, retention, stress, and training needs: National survey results.

Aggression and violence against educators and school personnel have raised public health concerns that require attention from researchers, policymakers, and training providers in U.S. schools. School aggression and violence have negative effects on school personnel health and retention and on student achievement and development. In partnership with several national organizations, the American Psychological Association (APA) Task Force on Violence Against Educators and School Personnel administered two national, multi-informant, cross-sectional surveys. Time 1 data were collected in 2020-2021 from 14,966 respondents; participants reflected on their experiences of violence and aggression before COVID-19 and during COVID-19 restrictions in this survey. One year later, in 2022, 11,814 respondents completed the Time 2 survey after COVID-19 restrictions ended. Participants included teachers, school psychologists, social workers, counselors, staff members, and administrators from all 50 states and Puerto Rico. Rates of violence and aggression directed against educators by students, parents, colleagues, and administrators were substantial before COVID-19, were lower during COVID-19 restrictions, and returned to prepandemic levels or higher after COVID-19 restrictions. After COVID-19 restrictions, 22%-80% of respondents reported verbal or threatening aggression, and 2%-56% of respondents reported physical violence at least once during the year, varying by stakeholder role and aggressor. Rates of intentions to quit the profession ranged from 21% to 43% during COVID-19 restrictions (2020-2021) and from 23% to 57% after COVID-19 restrictions (2021-2022), varying by stakeholder role. Participants across roles reported substantial rates of anxiety and stress, especially during and after COVID-19 restrictions, and identified specific training needs. Implications for theory, research, training, and policy are presented. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Post-operative pain in non-surgical root canal treatment after sealer-based obturation versus warm vertical compaction: A randomized clinical trial.

AIM: Post-operative pain may occur after non-surgical root canal treatment (NSRCT). The root filling technique and choice of sealer may be contributing factors. This randomized controlled clinical trial compared post-operative pain and analgesics intake after NSRCT using a sealer-based obturation technique (SBO) with single-cone gutta-percha and calcium silicate sealer (CSS) versus a warm-vertical compaction (WVC) technique with gutta-percha and a resin-based sealer (RBS). METHODOLOGY: This study was designed as a parallel-two arm, double-blind, randomized superiority clinical trial registered at www. CLINICALTRIALS: gov (NCT04753138). Patients referred for NSRCT fulfilling the inclusion criteria participated in this study. Pre-operative periapical radiographs and CBCT scans were taken and numerical rating scale (NRS) pain scores were recorded. Upon completion of canal instrumentation, participants were randomly allocated to either Group SBO: SBO with CSS or Group WVC: Warm-vertical compaction with RBS. Post-operative pain and analgesics intake were recorded at 1, 3 and 7 days after endodontic treatment completion. Non-parametric Mann-Whitney U and Friedman tests and a generalized estimating equation were used to assess differences in pain scores between the groups, within each treatment group at different time points and for correlations, respectively. RESULTS: The study included 195 participants (212 teeth). One participant declined to submit the NRS form. Therefore, 194 participants (211 teeth) were included in the final analysis (99.5% response rate). No statistically significant differences in post-operative pain or analgesic intake existed between the two groups at any time point (p > .05). Age, pre-operative pain, apical diagnosis and post-operative analgesic intake were significantly related to post-operative pain (p < .05). CONCLUSIONS: Sealer-based obturation technique with CSS was associated with similar post-operative pain levels and analgesics intake as WVC with RBS. Regarding post-operative pain, SBO with CSSs may be a suitable clinical alternative.