Accurate path integration in continuous attractor network models of grid cells

Grid cells in the rat entorhinal cortex display strikingly regular firing responses to the animal's position in 2-D space and have been hypothesized to form the neural substrate for dead-reckoning. However, errors accumulate rapidly when velocity inputs are integrated in existing models of grid cell activity. To produce grid-cell-like responses, these models would require frequent resets triggered by external sensory cues. Such inadequacies, shared by various models, cast doubt on the dead-reckoning potential of the grid cell system. Here we focus on the question of accurate path integration, specifically in continuous attractor models of grid cell activity. We show, in contrast to previous models, that continuous attractor models can generate regular triangular grid responses, based on inputs that encode only the rat's velocity and heading direction. We consider the role of the network boundary in the integration performance of the network and show that both periodic and aperiodic networks are capable of accurate path integration, despite important differences in their attractor manifolds. We quantify the rate at which errors in the velocity integration accumulate as a function of network size and intrinsic noise within the network. With a plausible range of parameters and the inclusion of spike variability, our model networks can accurately integrate velocity inputs over a maximum of ~10–100 meters and ~1–10 minutes. These findings form a proof-of-concept that continuous attractor dynamics may underlie velocity integration in the dorsolateral medial entorhinal cortex. The simulations also generate pertinent upper bounds on the accuracy of integration that may be achieved by continuous attractor dynamics in the grid cell network. We suggest experiments to test the continuous attractor model and differentiate it from models in which single cells establish their responses independently of each other

Strategies to diagnose ovarian cancer: new evidence from phase 3 of the multicentre international IOTA study

Background: To compare different ultrasound-based international ovarian tumour analysis (IOTA) strategies and risk of malignancy index (RMI) for ovarian cancer diagnosis using a meta-analysis approach of centre-specific data from IOTA3. Methods: This prospective multicentre diagnostic accuracy study included 2403 patients with 1423 benign and 980 malignant adnexal masses from 2009 until 2012. All patients underwent standardised transvaginal ultrasonography. Test performance of RMI, subjective assessment (SA) of ultrasound findings, two IOTA risk models (LR1 and LR2), and strategies involving combinations of IOTA simple rules (SRs), simple descriptors (SDs) and LR2 with and without SA was estimated using a meta-analysis approach. Reference standard was histology after surgery. Results: The areas under the receiver operator characteristic curves of LR1, LR2, SA and RMI were 0.930 (0.917–0.942), 0.918 (0.905–0.930), 0.914 (0.886–0.936) and 0.875 (0.853–0.894). Diagnostic one-step and two-step strategies using LR1, LR2, SR and SD achieved summary estimates for sensitivity 90–96%, specificity 74–79% and diagnostic odds ratio (DOR) 32.8–50.5. Adding SA when IOTA methods yielded equivocal results improved performance (DOR 57.6–75.7). Risk of Malignancy Index had sensitivity 67%, specificity 91% and DOR 17.5. Conclusions: This study shows all IOTA strategies had excellent diagnostic performance in comparison with RMI. The IOTA strategy chosen may be determined by clinical preference

Hormonal Contraception and Bone Metabolism: Emerging Evidence from a Systematic Review and Meta-Analysis of Studies on Post-Pubertal and Reproductive-Age Women

Background/Objectives: This study aims to assess the effects of combined hormonal contraceptives (CHCs) on bone metabolism markers. It primarily measures osteocalcin and additionally examines other bone health markers, seeking to determine their responses to estrogen–progestogen treatments. Methods: This study involved a comprehensive evaluation of the pertinent literature and a meta-analysis explicitly conducted on data describing women of reproductive age. The analysis encompassed accessible papers ranging to December 2024 (i.e., those listed in PubMed/Medline, Embase, Scopus, the Cochrane Database, International Clinical Trials Registry, and ClinicalTrials.gov). We examined published randomized controlled trials (RCTs) and prospective studies. The quality of the studies was assessed using the Cochrane tool for RCTs and the Newcastle–Ottawa Scale for prospective studies. The selected indicators for primary and secondary outcomes were ascertained by standardized mean change (SMC), displaying the difference between conditions before and after treatment. Trends were evaluated using meta-regressions. Results: Ultimately, 34 articles out of 1924 identified items met the inclusion criteria, covering 33 unique studies. In EE/E4 combinations, osteocalcin dropped significantly (SMC −0.54 (CI.95 −0.64/−0.43) and −0.43 (CI.95 −0.76/−0.10)). Similar effects were observed for other bone-formation and reabsorption markers, with less significant reductions observed in E2-containing CHC (e.g., alkaline phosphatase (bone) EE combinations, SMC −0.39 (CI.95 −0.67/−0.11); P1NP E2 combination, 0.12 (CI.95 −0.10/0.33); and EE combinations, −0.55 (CI.95 −0.83/−0.26)). The reduction patterns also exhibited differences according to the women’s age (e.g., osteocalcin in EE combinations ≤21, SMC −0.63 (CI.95 −0.77/−0.49) and >21, SMC −0.42 (CI.95 −0.61/−0.24); alkaline phosphatase (bone) EE combinations ≤21, SMC −0.55 (CI.95 −0.86/−0.24) and >21, SMC −0.06 (CI.95 −0.47/0.35)). This analysis found that CHC maintains or reduces bone turnover in childbearing women, with effects varying by age and hormone combination. Moreover, bone-formation and reabsorption markers correlated positively to pro-androgenic progestins (p < 0.05). Thus, estrogen–progestogen combinations reduce bone turnover less when weak estrogens and a pro-androgenic or neutral progestin are present. Conclusions: This study found that CHCs reduce bone turnover, with natural estrogens and androgenic progestins appearing to be more beneficial than EE and anti-androgenic types. These findings would potentially influence decisions relevant to CHC prescriptions during a woman’s reproductive phases, emphasizing the need for additional research to tailor CHC usage to bone health

Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.

OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity

Supplementations of industrial multichamber parenteral nutrition bags in critically ill children: safety of the practice

Parenteral nutrition (PN) is sometimes required in critically ill children because of contraindication or intolerance to full enteral nutrition. European guidelines recommend favoring multichamber bag PN (MCB PN), when possible, for quality purposes and ease of use. The prescribers may adjust the MCB PN through supplementations to better fulfill patient needs. The objective of this study is to investigate the use and supplementations of MCB PN. This observational, single-center, retrospective study was conducted in a pediatric intensive care unit (PICU). We collected prescriptions of MCB PNs and their supplementations added directly into PN bags. A descriptive analysis and a comparison of electrolyte supplementations with the manufacturer's recommendations were undertaken. One hundred thirty-five children (median age 39.2 months [7.0-118.8]) were included, 1449 MCB PNs were administered, and 1652 supplementations were carried out in 736 PN bags. Thirty-two percent of supplementations were vitamins, 32.2% were trace elements, and 35.8% were electrolytes. Around 10% of electrolyte supplementations in PN bags were outside the manufacturer's recommendations. These nonconformities primarily concerned phosphate. This study showed the real-world clinical use of MCB PN in the PICU. Proper attention should be paid to septic risks and physicochemical risks to ensure efficient practice and safety of MCB PN use. [Abstract copyright: © 2022 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.

Solutions for global marine litter pollution

Since the 1950s the amount of plastics in the marine environment has increased dramatically. Worldwide there is a growing concern about the risks and possible adverse effects of (micro) plastics. This paper reflects on the sources and effects of marine litter and the effects of policies and other actions taken worldwide. Current knowledge offers a solid basis for effective action. Yet, so far the effects of policies and other initiatives are still largely insufficient. The search for appropriate responses could be based on possible interventions and profound understanding of the context specific factors for success. Moreover, the scope, timeframe and dynamics of all initiatives are distinctly different and orchestration at all levels, in close cooperation with one another is currently lacking

Process development and validation of expanded regulatory T cells for prospective applications: an example of manufacturing a personalized advanced therapy medicinal product

Background: A growing number of clinical trials have shown that regulatory T (Treg) cell transfer may have a favorable effect on the maintenance of self-tolerance and immune homeostasis in different conditions such as graft-versus-host disease (GvHD), solid organ transplantation, type 1 diabetes, and others. In this context, the availability of a robust manufacturing protocol that is able to produce a sufficient number of functional Treg cells represents a fundamental prerequisite for the success of a cell therapy clinical protocol. However, extended workflow guidelines for nonprofit manufacturers are currently lacking. Despite the fact that different successful manufacturing procedures and cell products with excellent safety profiles have been reported from early clinical trials, the selection and expansion protocols for Treg cells vary a lot. The objective of this study was to validate a Good Manufacturing Practice (GMP)-compliant protocol for the production of Treg cells that approaches the whole process with a risk-management methodology, from process design to completion of final product development. High emphasis was given to the description of the quality control (QC) methodologies used for the in-process and release tests (sterility, endotoxin test, mycoplasma, and immunophenotype). Results: The GMP-compliant protocol defined in this work allows at least 4.11 7 109 Treg cells to be obtained with an average purity of 95.75 \ub1 4.38% and can be used in different clinical settings to exploit Treg cell immunomodulatory function. Conclusions: These results could be of great use for facilities implementing GMP-compliant cell therapy protocols of these cells for different conditions aimed at restoring the Treg cell number and function, which may slow the progression of certain diseases