Accuracy assessment of ChatGPT responses to frequently asked questions regarding anterior cruciate ligament surgery.

BACKGROUND: The emergence of artificial intelligence (AI) has allowed users to have access to large sources of information in a chat-like manner. Thereby, we sought to evaluate ChatGPT-4 response's accuracy to the 10 patient most frequently asked questions (FAQs) regarding anterior cruciate ligament (ACL) surgery. METHODS: A list of the top 10 FAQs pertaining to ACL surgery was created after conducting a search through all Sports Medicine Fellowship Institutions listed on the Arthroscopy Association of North America (AANA) and American Orthopaedic Society of Sports Medicine (AOSSM) websites. A Likert scale was used to grade response accuracy by two sports medicine fellowship-trained surgeons. Cohen's kappa was used to assess inter-rater agreement. Reproducibility of the responses over time was also assessed. RESULTS: Five of the 10 responses received a 'completely accurate' grade by two-fellowship trained surgeons with three additional replies receiving a 'completely accurate' status by at least one. Moreover, inter-rater reliability accuracy assessment revealed a moderate agreement between fellowship-trained attending physicians (weighted kappa = 0.57, 95% confidence interval 0.15-0.99). Additionally, 80% of the responses were reproducible over time. CONCLUSION: ChatGPT can be considered an accurate additional tool to answer general patient questions regarding ACL surgery. None the less, patient-surgeon interaction should not be deferred and must continue to be the driving force for information retrieval. Thus, the general recommendation is to address any questions in the presence of a qualified specialist.

Is it really over when it is over? physical, mental and emotional health status of long-term breast cancer survivors compared to healthy matched controls.

PURPOSE: This study aimed to assess pain, fitness condition, physical activity (PA) level, comorbidities, cancer-related fatigue (CRF), mood state and health-related quality of life (HRQoL) in long-term breast cancer survivors (LTBCS) compared to women without cancer history, matched by age, weight, height, and educational level. METHODS: A cross-sectional study conducted in Granada between April 2018 and July 2023 involved 80 LTBCS and 80 matched controls. Pain, fitness condition, PA level, comorbidities, CRF, mood state, and HRQoL were evaluated ≥ 5 years post-diagnosis using validated instruments. RESULTS: LTBCS, compared to the controls, reported significantly higher levels of "pain intensity and interference", CRF (in all domains and > 40% exhibited moderate-to-severe fatigue levels), "sadness-depression", "anxiety", "anger/hostility", and "symptom scales" (All: P = .000 to .027). Moreover, 66.25% of LTBCS not only did not reach recommended PA levels (P = .035), but also presented significantly lower levels of "general physical fitness", "muscular strength", "happiness", "functioning scales" (except "emotional functioning"), and "global health status" (All: P = .000 to .048). CONCLUSION: LTBCS still suffer from physical (pain, fitness condition, and CRF), both mental and emotional (sadness-depression, anxiety and anger/hostility) long-term side effects as well as multiple HRQoL issues (including lower levels of physical functioning and higher levels of symptoms). These findings highlight the chronic nature of this disease and the importance of continuing long- term follow-up care for survivors many years after the diagnosis of breast cancer.

Postoperative Feeding in Cleft Surgery: A Systematic Review.

INTRODUCTION: Postoperative feeding is crucial for the recovery of children after cleft surgery. The literature outlines diverse feeding methods with varying recommendations on the duration of non-nipple feeding postsurgery. This study aims to explore reported postoperative feeding modalities for infants undergoing primary cleft lip/palate repair, concentrating on their influence on feeding improvement and complication reduction. METHODS: PubMed, Cochrane, and Web of Science databases were queried for original English articles without any date restrictions. This review was conducted in accordance with the 2020 PRISMA. The MINORS criteria was used to assess quality of studies. RESULTS: Of 696 abstracts, 9 full-text articles were included, consisting of 459 children with cleft lip (n = 221) & cleft lip/palate (n = 238). Feeding modalities included bottle, breastfeeding, spoon, syringe, and nasogastric tube. Two studies found a significant increase in weight with breastfeeding compared to spoon or cup. Two studies found partial wound dehiscence using spoons, and two studies reported dehiscence using bottles. Post-palatoplasty, two studies showed a decrease in hospital stay in infants breastfed (2.1 & 5.8 days) vs spoon-fed (6 days). Analgesia was reduced in the breastfed group vs spoon/nasogastric tube. CONCLUSION: This review highlights the importance of postoperative feeding in the recovery of infants with cleft lip/palate. Evidence suggests that breastfeeding may offer advantages in terms of weight gain and reduced hospital stay, while potentially minimizing the need for postoperative analgesia. The limited number of studies and variability in their outcomes underscore the need for further research to establish evidence-based guidelines for postoperative feeding.

Anterior Cruciate Ligament Repair Results in Similar Patient Reported Outcome Measures as Anterior Cruciate Ligament Reconstruction: A Systematic Review of Prospective Comparative Studies.

PURPOSE: To investigate the patient-reported outcomes (PROs), knee stability, and complications in prospective comparative studies of patients undergoing augmented anterior cruciate ligament (ACL) repair compared to ACL reconstruction (ACLR). METHODS: A literature search was performed according to the 2020 PRISMA guidelines. Human clinical studies of level I-II evidence comparing PROs, knee stability and complications following ACL repair and reconstruction were included, and a qualitative analysis was performed. Excluded studies included those lacking reporting outcomes, studies that performed open ACLR or repair, studies published prior to the year 2000 and studies with evidence levels III-IV. Study quality was assessed using the Cochrane Collaboration's risk of bias tool. RESULTS: Seven level of evidence I-II studies were retained including 190 ACLR and 221 repairs (75 Bridge-Enhanced ACL Repair (BEAR), 49 Suture Augmentation (SA), and 97 Dynamic Intraligamentary Stabilization (DIS)). At final follow-up, re-rupture rates varied between 0-14% (BEAR) vs 0-6% (ACLR) and mean side-to-side differences measured using KT-1000 testing ranged from 1.6-1.9mm (BEAR) vs 1.7-3.14mm (ACLR). For DIS vs ACLR, mean anterior tibial translation values at final follow-up were 1.7mm (DIS) vs. 1.4mm (ACLR), and re-rupture rates ranged from 20.8%-29% (DIS) vs. 17%-27.2% (ACLR). For SA vs ACLR, the mean side to side difference ranged from 0.2-0.39mm (SA) vs 0.33-0.4mm (ALCR), while the re-rupture rates were 10% (SA) vs. 0% (ACLR). International Knee Documentation Committee (IKDC), Tegner, Lysholm and Knee Injury and Osteoarthritis Outcome (KOOS) scores across both cohorts exhibited statistically significant, and comparable improvement, from baseline to final follow-up ranging from 1 to 5 years. CONCLUSION: Augmented ACL repair results in similar patient reported outcomes measures in comparison to ACL reconstruction. However, augmented ACL repair may be associated with higher rates of failure given re-rupture rates of up to 14%, 29% and 10% for BEAR, DIS and SA, respectively. LEVEL OF EVIDENCE: II; Systematic review of level I-II studies.

bio2Byte Tools deployment as a Python package and Galaxy tool to predict protein biophysical properties.

SUMMARY: We introduce a unified Python package for the prediction of protein biophysical properties, streamlining previous tools developed by the Bio2Byte research group. This suite facilitates comprehensive assessments of protein characteristics, incorporating predictors for backbone and sidechain dynamics, local secondary structure propensities, early folding, long disorder, beta-sheet aggregation, and fused in sarcoma (FUS)-like phase separation. Our package significantly eases the integration and execution of these tools, enhancing accessibility for both computational and experimental researchers. AVAILABILITY AND IMPLEMENTATION: The suite is available on the Python Package Index (PyPI): https://pypi.org/project/b2bTools/ and Bioconda: https://bioconda.github.io/recipes/b2btools/README.html for Linux and macOS systems, with Docker images hosted on Biocontainers: https://quay.io/repository/biocontainers/b2btools?tab=tags&tag=latest and Docker Hub: https://hub.docker.com/u/bio2byte. Online deployments are available on Galaxy Europe: https://usegalaxy.eu/root?tool_id=b2btools_single_sequence and our online server: https://bio2byte.be/b2btools/. The source code can be found at https://bitbucket.org/bio2byte/b2btools_releases.

Field-Free Spin-Orbit Torque Switching in Janus Chromium Dichalcogenides.

We predict a very large spin-orbit torque (SOT) capability of magnetic chromium-based transition-metal dichalcogenide (TMD) monolayers in their Janus forms CrXTe, with X = S, Se. The structural inversion symmetry breaking, inherent to Janus structures is responsible for a large SOT response generated by giant Rashba splitting, equivalent to that obtained by applying a transverse electric field of ∼100 V nm-1 in non-Janus CrTe2, completely out of experimental reach. By performing transport simulations on carefully derived Wannier tight-binding models, Janus systems are found to exhibit an SOT performance comparable to the most efficient two-dimensional materials, while additionally allowing for field-free perpendicular magnetization switching, due to their reduced in-plane symmetry. Altogether, our findings evidence that magnetic Janus TMDs stand as suitable candidates for ultimate SOT-MRAM devices in an ultracompact self-induced SOT scheme.

Predicting peritumoral glioblastoma infiltration and subsequent recurrence using deep-learning-based analysis of multi-parametric magnetic resonance imaging.

Purpose: Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. Approach: We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. Results: Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). Conclusions: The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

Evaluation of the potential use of protoporphyrins as biomarkers of anemic disease in human urine from inflammatory bowel disease patients.

Protoporphyrins are organic compounds with cyclic structure that are synthesised by a wide variety of organisms. In humans, these compounds are detected in blood and urine, with significantly higher levels in blood. Their potential as biomarkers of anemia and other diseases is currently being investigated, as their levels change according to the biochemical processes associated with the disease. The most widely used biomarker of anemia is serum ferritin, but it is unreliable in patients with inflammatory bowel disease (IBD) because its levels can be altered by acute inflammation and/or infections. There is therefore a need to look for new markers to help diagnose anemia in IBD patients. This work develops and validates a method for the determination of three protoporphyrins in human urine: protoporphyrin IX (PPIX), protoporphyrin IX complex with Zn (ZnPPIX) and protoporphyrin IX complex with Fe (II) (FePPIX), the latter also known as heme. The aim is to evaluate their potential as biomarkers of anemic disease in patients diagnosed with IBD. The proposed analytical method is based on high performance liquid chromatography (HPLC) with dual detection based on photodiode array (PDA) and fluorescence (FD). Quantification of the analytes at very low concentrations is possible due to the efficient preconcentration provided by dispersive liquid-liquid microextraction (DLLME) and the sensitivity of the detection systems. The method was validated by evaluating linearity (25-1000 ng mL-1), matrix effect, sensitivity (limits of quantification were between 5 and 11 ng mL-1), selectivity, accuracy, carry-over, dilution integrity, stability and precision (< 12.1 %). Finally, statistical analyses applied to the sample quantification results showed these three markers, together with five clinical markers, were significantly different between anemic and non-anemic IBD patients.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. METHODS: This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. FINDINGS: At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. CONCLUSIONS: T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. FUNDING: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

ACL Reconstruction in Patients Over Fifty Years of Age Results in Improvements in Functional Outcomes and Broad Complication Rates: A Systematic Review.

PURPOSE: To assess the patient-reported outcomes measures (PROMs), functional knee measures, and incidence of complications in patients aged 50 and older undergoing anterior cruciate ligament reconstruction (ACLR). METHODS: A literature search was conducted across PubMed, Embase, and Scopus databases, spanning from their inception to November 2023, in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Inclusion criteria consisted of clinical studies reporting PROMs, measures of knee stability, and complication rates, following ACLR in patients aged ≥ 50 with minimum 2 year follow-up. The Methodological Index for Non-Randomized Studies (MINORS) criteria was used to assess study quality. Primary outcome measures consisted of changes PROMs and complication rates following ACLR. RESULTS: A total of 17 studies, consisting of 1,163 patients undergoing ACLR were identified. Autografts were utilized in 90.3% of patients, compared to 9.7% of patients treated using allografts. At minimum 24-month follow-up, the mean International Knee Documentation Score (IKDC) ranged from 67.4 to 92.96, while mean Lysholm scores ranged from 84.4 to 94.8, and mean Tegner scores ranged from 0.3 to 5.4. The mean side to side difference at final follow-up ranged from 1.2 to 2.4mm while the rates of recurrent instability ranged from 0 to 18%. Complications and revisions ranged from 0% to 40.4% and 0% to 37.5% of cases, with the highest rates observed in studies noting a high incidence of intraoperative cartilage lesions. CONCLUSION: Anterior cruciate ligament reconstruction in patients above the age of 50 results in favorable IKDC, Lysholm and Tegner activity scores and improvements in functional knee measures. However, a wide range of reoperation and complications are reported, attributed to varying levels of chondral injury and osteoarthritis which warrant consideration when discussing expectations in patients 50 and above undergoing ACLR. LEVEL OF EVIDENCE: IV, Systematic Review of Level II-IV studies.

The Prevalence of HIV Seroconversion in Healthcare Workers Following Sharp Injuries and Exposure to Biofluids.

Background and objective Workplace accidents (WPAs) are a common problem worldwide. They are often considered a public health concern due to the potential transmission of infections such as HIV, hepatitis B, and hepatitis C through sharp devices or direct exposure to biofluids. Post-exposure prophylaxis (PEP) has demonstrated effectiveness in such instances, especially immediately after exposure. The present study aimed to report the prevalence rate of HIV seroconversion following such exposure among healthcare workers (HCWs). Methods We conducted a cross-sectional study involving a database analysis of cases from 2015 to 2024. Central tendency measures were used to describe population characteristics, and rates were calculated using standard methods. Results A total of 514 HCWs were included in the study. The prevalence of WPAs was 13 per 100 HCWs. Regarding WPAs related to HIV exposure, the prevalence was 0.9 per 100 HCWs, with 0% seroconversion thanks to timely PEP. Conclusions WPAs related to HIV exposure are a serious issue for public health systems worldwide. Although protocols are available and no seroconversion cases were reported in the present study, PEP is not always accessible in several settings, increasing the risk of seroconversion. International public policy measures should be uniformly implemented to provide faster access to prophylaxis, educate the personnel, raise awareness about bloodborne diseases, and reduce excessive red tape.

Sacituzumab govitecan for hormone receptor-positive HER2-negative advanced breast cancer.

INTRODUCTION: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody-drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC. AREAS COVERED: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT. EXPERT OPINION: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

PURPOSE: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). METHODS: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. RESULTS: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. CONCLUSIONS: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Improving the production of 22-hydroxy-23,24-bisnorchol-4-ene-3-one in Mycolicibacterium smegmatis.

The 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC) is a C22 steroid synthon of pharmaceutical interest that can be produced as a lateral end-product of the catabolism of natural sterols (e.g., cholesterol or phytosterols). This work studies the role of an aldehyde dehydrogenase coded by the MSMEG_6563 gene of Mycolicibacterium smegmatis, named msRed, in 4-HBC production. This gene is located contiguously to the MSMEG_6561 encoding the aldolase msSal which catalyses the retroaldol elimination of acetyl-CoA of the metabolite intermediate 22-hydroxy-3-oxo-cholest-4-ene-24-carboxyl-CoA to deliver 3-oxo-4-pregnene-20-carboxyl aldehyde (3-OPA). We have demonstrated that msRed reduces 3-OPA to 4-HBC. Moreover, the role of msOpccR reductase encoded by MSMEG_1623 was also explored confirming that it also performs the reduction of 3-OPA into 4-HBC, but less efficiently than msRed. To obtain a M. smegmatis 4-HBC producer strain we deleted MSMEG_5903 (hsd4A) gene in strain MS6039-5941 (ΔkshB1, ΔkstD1) that produces 4-androstene-3,17-dione (AD) from natural sterols (cholesterol or phytosterols). The triple MS6039-5941-5903 mutant was able to produce 9 g/L of 4-HBC from 14 g/L of phytosterols in 2 L bioreactor, showing a productivity of 0.140 g/L h-1. To improve the metabolic flux of sterols towards the production of 4-HBC we have cloned and overexpressed the msSal and msRed enzymes in the MS6039-5941-5903 mutant rendering a production titter of 12.7 g/L with a productivity of 0.185 g/L h-1, and demonstrating that the new recombinant strain has a great potential for its industrial application.

Out-of-equilibrium dynamics of a grid-like Fe(ii) spin crossover dimer triggered by a two-photon excitation.

The application of two-photon excitation (TPE) in the study of light-responsive materials holds immense potential due to its deeper penetration and reduced photodamage. Despite these benefits, TPE has been underutilised in the investigation of the photoinduced spin crossover (SCO) phenomenon. Here, we employ TPE to delve into the out-of-equilibrium dynamics of a SCO FeII dimer of the form [FeII(HL)2]2(BF4)4·2MeCN (HL = 3,5-bis{6-(2,2'-bipyridyl)}pyrazole). Optical transient absorption (OTA) spectroscopy in solution proves that the same dynamics take place under both one-photon excitation (OPE) and TPE. The results show the emergence of the photoinduced high spin state in less than 2 ps and with a lifetime of 147 ns. Time-resolved photocrystallography (TRXRD) reveals a single molecular reorganisation within the first 500 ps following TPE. Additionally, variable temperature single crystal X-ray diffraction (VTSCXRD) and magnetic susceptibility measurements confirm that the thermal transition is silenced by the solvent. While the results of the OTA and TRXRD utilising TPE are intriguing, the high pump fluencies required to excite enough metal centres to the high spin state may impair its practical application. Nonetheless, this study sheds light on the potential of TPE for the investigation of the out-of-equilibrium dynamics of SCO complexes.

Intergenerational effects of maternal childhood maltreatment on newborns' stress regulation: The role of maternal depressive symptoms.

BACKGROUND: Maternal childhood maltreatment (CM) has been repeatedly associated with negative offspring's emotional outcomes. The dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis has emerged as the main underlying physiological mechanism. OBJECTIVE: To explore the association between maternal CM and newborns' physiological and neurobehavioral stress responses, considering the role of perinatal maternal depression and bonding. PARTICIPANTS AND SETTING: 150 healthy women were followed throughout pregnancy. 79 mother-infant dyads were included in the final analyses. Maternal CM was evaluated using the Childhood Trauma Questionnaire and depressive symptoms by the Edinburgh Postnatal Depression Scale (EPDS) at each trimester. At 7 weeks postpartum, the EPDS and the Postpartum Bonding Questionnaire were administered. Newborns' behavioral responses were assessed using "States Organization" (SO) and "States Regulation" (SR) subdomains of the Neonatal Behavioral Assessment Scale (NBAS). Newborns' salivary samples were collected before and after the NBAS to study cortisol reactivity. METHODS: A cross-lagged panel model was employed. RESULTS: Infants born to mothers with higher CM presented more optimal scores on SO (ß (0.635) = 0.216, p ã€ˆ001) and SR (ß (0.273) = 0.195, p = .006), and a higher cortisol reactivity after NBAS handling (ß(0.019) = 0.217, p = .009). Moreover, newborns of mothers with higher CM and postpartum depressive symptoms exhibited a poorer performance on SR (ß (0.156 = -0.288,p = .002). Analyses revealed non-significant relationships between mother-infant bonding, newborns' cortisol reactivity and SO. CONCLUSIONS: Newborns from mothers with greater CM present higher cortisol reactivity and more optimal behavioral responses, which may reflect a prenatal HPA axis sensitization. However, those exposed to maternal postnatal depressive symptoms present poorer stress recovery.

Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties.

5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.

Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics.

Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.

Diffusion and Interaction Effects On Molecular Release Kinetics From Collapsed Microgels.

The efficient transport of small molecules through dense hydrogel networks is crucial for various applications, including drug delivery, biosensing, catalysis, nanofiltration, water purification, and desalination. In dense polymer matrices, such as collapsed microgels, molecular transport follows the solution-diffusion principle: Molecules dissolve in the polymeric matrix and subsequently diffuse due to a concentration gradient. Employing dynamical density functional theory (DDFT), we investigate the nonequilibrium release kinetics of nonionic subnanometer-sized molecules from a microgel particle, using parameters derived from prior molecular simulations of a thermoresponsive hydrogel. The kinetics is primarily governed by the microgel radius and two intensive parameters: the diffusion coefficient and solvation free energy of the molecule. Our results reveal two limiting regimes: a diffusion-limited regime for large, slowly diffusing, and poorly soluble molecules within the hydrogel; and a reaction-limited regime for small, rapidly diffusing, and highly soluble molecules. These principles allow us to derive an analytical equation for release time, demonstrating excellent quantitative agreement with the DDFT results-a valuable and straightforward tool for predicting release kinetics from microgels.