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The chemiluminescent light-emission pathway of phenoxy-1,2-dioxetane luminophores attracts growing interest within the scientific community. Dioxetane probes undergoing rapid flash-type chemiexcitation exhibit higher detection sensitivity than those with a slow glow-type chemiexcitation rate. We discovered that dioxetanes fused to non-strained six-member rings, with hetero atoms or inductive electron-withdrawing groups, present both accelerated chemiexcitation rates and elevated chemical stability compared to dioxetanes fused to four-member strained rings. DFT computational simulations supported the chemiexcitation acceleration observed by spiro-fused six-member rings with inductive electron-withdrawing groups of dioxetanes. Specifically, a spiro-dioxetane with a six-member sulfone ring exhibited a chemiexcitation rate 293-fold faster than that of spiro-adamantyl-dioxetane. A turn-ON dioxetane probe for the detection of the enzyme β-galactosidase, containing the six-member sulfone unit, exhibited a S/N value of 108 in LB cell growth medium. This probe demonstrated a substantial increase in detection sensitivity towards E. coli bacterial cells expressing β-galactosidase, with an LOD value that is 44-fold more sensitive than that obtained by the adamantyl counterpart. The accelerated chemiexcitation and the elevated chemical stability presented by dioxetane containing a spiro-fused six-member ring with a sulfone inductive electron-withdrawing group, make it an ideal candidate for designing efficient turn-on chemiluminescent probes with exceptionally high detection sensitivity., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Negative symptoms in schizophrenia (SZ), such as apathy and diminished expression, have limited treatments and significantly impact daily life. Our study focuses on the functional division of the striatum: limbic-motivation and reward, associative-cognition, and sensorimotor-sensory and motor processing, aiming to identify potential biomarkers for negative symptoms., Study Design: This longitudinal, 2-center resting-state-fMRI (rsfMRI) study examines striatal seeds-to-whole-brain functional connectivity. We examined connectivity aberrations in patients with schizophrenia (PwSZ), focusing on stable group differences across 2-time points using intra-class-correlation and associated these with negative symptoms and measures of cognition. Additionally, in PwSZ, we used negative symptoms to predict striatal connectivity aberrations at the baseline and used the striatal aberration to predict symptoms 9 months later., Study Results: A total of 143 participants (77 PwSZ, 66 controls) from 2 centers (Berlin/Geneva) participated. We found sensorimotor-striatum and associative-striatum hypoconnectivity. We identified 4 stable hypoconnectivity findings over 3 months, revealing striatal-fronto-parietal-cerebellar hypoconnectivity in PwSZ. From those findings, we found hypoconnectivity in the bilateral associative striatum with the bilateral paracingulate-gyrus and the anterior cingulate cortex in PwSZ. Additionally, hypoconnectivity between the associative striatum and the superior frontal gyrus was associated with lower cognition scores in PwSZ, and weaker sensorimotor striatum connectivity with the superior parietal lobule correlated negatively with diminished expression and could predict symptom severity 9 months later., Conclusions: Importantly, patterns of weaker sensorimotor striatum and superior parietal lobule connectivity fulfilled the biomarker criteria: clinical significance, reflecting underlying pathophysiology, and stability across time and centers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Psychological stress has been suggested as a contributory factor in the onset and progression of multiple sclerosis (MS). The 7 October 2023 terrorist attacks in Israel caused significant psychological stress, providing a unique context to study its impact on MS activity. This study aims to assess the impact of war-related psychological stress on MS activity using magnetic resonance imaging (MRI) scans and clinical follow-up., Methods: This observational retrospective case-control study includes 93 patients with MS (pwMS) who had routine annual MRI scans from three periods (7 October 2021 to 7 January 2022; 7 October 2022 to 7 January 2023; and 7 October 2023 to 7 January 2024). Data were collected from medical records and MRI scans at Hadassah Medical Center. MRI scans were classified as active if new or enlarging T2 lesions and/or enhancing T1 lesions were present., Results: MRI activity significantly increased among pwMS during the first 3 months of the war compared to the corresponding period in the preceding year (11/93 vs. 23/93, P = 0.0139), with an OR of 4.0 (95% confidence interval: 1.29-16.442). pwMS with an EDSS score ≥4 showed a significant increase in MRI activity (P = 0.045), whereas no significant increase was observed in patients with an EDSS score ≤3.5 (P = 0.23). Additionally, MRI activity increased later during the war compared to the previous year (P < 0.0001)., Interpretation: This study provides evidence of increased MRI-detected disease activity in pwMS during periods of war-related psychological stress. Our findings highlight the importance of considering psychological stress in MS management. Healthcare providers should be aware of the potential for increased disease activity in pwMS during extreme stress and may consider more frequent monitoring, including MRI scans, or treatment adjustments during such periods., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Extracting regularities and probabilities from the environment is a fundamental and critical ability in an ever-changing surrounding. Previous findings showed that people are highly efficient in learning these regularities and that emotional stimuli are better learned than neutral ones. Yet, the generality and the underlying mechanism of this benefit are poorly understood. Here, participants viewed a stream of images with negative and neutral valence. Unbeknownst, the items recurred in regularity as triplets. Then, to assess learning, a surprised familiarity test was conducted. The results of Experiment 1, using two sets of stimuli, found better statistical learning for negative triplets than for neutral triplets. Experiment 2 revealed similar benefits even when only a single negative item was in the triplet at the second or third position, suggesting the advantage is not cumulative. We speculated that the predictability of the negative items is driving the effect. Consequently, Experiment 3 confirmed that the memory for neutral items preceding negative items was better than for neutral items preceding neutral items. Together, these findings provide novel insights into the mechanism of how the learning of incidental temporal associations is influenced by negative stimuli and the role of predictability in the negative valence benefit.

Introduction/background: Peer-led teaching sessions (PLTS) supplement conventional medical education, allowing students to share knowledge effectively. PLTS have shown significant academic benefits for student instructors. However, the impact on attendees, especially concerning NBME-style examinations, remains underexplored., Methods: This study analyzed de-identified data from 67 first-year medical students at Kirk Kerkorian School of Medicine, divided into PLTS attendees (study group) and non-attendees (control group) based on session participation. Data were collected before two NBME examinations, with attendees defined as those attending at least five Peer-led teaching sessions. Academic performance was measured using NBME Customized Assessment Services (CAS) exam scores. Statistical analyses, including p-tests, chi-square, and t-tests, assessed differences in performance and potential biases based on MCAT scores, first-generation status, and socioeconomic background., Results: The study group initially had 26 students, and the control group had 31 students. Post-first examination, the study group adjusted to 22 students, and the control group to 35 students. MCAT scores and demographics showed no significant differences between groups. The first examination revealed a significant higher score in PLTS attendees' scores (4.28% increase, p = 0.036), indicating a positive impact of PLTS on basic science knowledge. The second examination on organ systems physiology showed no significant difference (p = 0.722)., Discussion: PLTS effectively enhance foundational science understanding but may be less impactful for advanced topics. The diminishing effect may result from increased use of diverse study resources and adaptation to medical school. Future research should explore long-term benefits, optimal implementation strategies, and the impact of instructor quality and engagement. Therefore, the overall conclusion is that PLTS positively influence NBME-style exam performance in early medical education, but benefits decrease over time., (© 2024. The Author(s).)

Extracellular vesicles (EVs) are released by all cells and hold great promise as a class of biomarkers. This promise has led to increased interest in measuring EV proteins from both total EVs as well as brain-derived EVs in plasma. However, measuring cargo proteins in EVs has been challenging because EVs are present at low levels, and EV isolation methods are imperfect at separating EVs from free proteins. Thus, knowing whether a protein measured after EV isolation is truly inside EVs is difficult. In this study, we developed methods to measure whether a protein is inside EVs and quantify the ratio of a protein in EVs relative to total plasma. To achieve this, we combined a high-yield size-exclusion chromatography protocol with an optimized protease protection assay and Single Molecule Array (Simoa) digital enzyme-linked immunoassays (ELISAs) for ultrasensitive measurement of proteins inside EVs. We applied these methods to analyze α-synuclein and confirmed that a small fraction of the total plasma α-synuclein is inside EVs. Additionally, we developed a highly sensitive Simoa assay for phosphorylated α-synuclein (phosphorylated at the Ser129 residue). We found enrichment in the phosphorylated α-synuclein to total α-synuclein ratio inside EVs relative to outside EVs. Finally, we applied the methods we developed to measure total and phosphorylated α-synuclein inside EVs from Parkinson's disease and Lewy body dementia patient samples. This work provides a framework for determining the levels of proteins in EVs and represents an important step in the development of EV diagnostics for diseases of the brain, as well as other organs., Competing Interests: Competing interests statement:D.R.W. is a founder, member of the Board of Directors, and equity holder in Quanterix. His interests were reviewed and are managed by BWH and Partners HealthCare in accordance with their conflict of interest policies. G.M.C. Disclosures: https://arep.med.harvard.edu/gmc/tech.html. The authors have filed IP on methods for EV isolation and analysis.

Objective: The aim of this study was to examine the obstetrical and neonatal outcomes in patients with gestational diabetes mellitus (GDM) who had postprandial glucose monitoring 1 vs. 2 h following meals., Study Design: In this prospective cohort study, we included patients with GDM who were referred to our medical center between July 2019 and June 2021. Patients chose the timing of postprandial glucose monitoring based on their own preferences. Obstetrical and neonatal outcomes, as well as patient satisfaction, were compared between patients who performed postprandial glucose monitoring 1 and 2 h after meals (PPG1 vs. PPG2). The primary outcome was birth weight. The study was powered to detect a 250 g increase in birth weight., Results: Overall, 99 patients were included: 50 in the PPG1 group and 49 in the PPG2 group. Baseline characteristics were comparable between the groups. Neonates in the PPG1 and PPG2 groups had similar birth weights (3319 ± 355 vs. 3319 ± 520 g, respectively, p = 0.99). Glycemic control, mode of delivery, gestational age at delivery, and satisfaction rates were also similar between the study groups., Conclusion: In patients with GDM, performing1 vs. 2 h following meals resulted in similar obstetrical and neonatal outcomes and similar satisfaction rates. We therefore recommend counseling patients to choose either strategy based on their personal preference., (© 2024. The Author(s).)

Protein kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer with two catalytic subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined post-mortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry and behavioural assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioural and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the catalytic subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The identification of Obstructive Sleep Apnea (OSA) is done by a Polysomnography test which is often done in later ages. Being able to notify potential insured members at earlier ages is desirable. For that, we develop predictive models that rely on Electronic Health Records (EHR) and predict whether a person will go through a sleep apnea test after the age of 50. A major challenge is the variability in EHR records in various insured members over the years, which this study investigates as well in the context of controls matching, and prediction. Since there are many temporal variables, the RankLi method was introduced for temporal variable selection. This approach employs the t-test to calculate a divergence score for each temporal variable between the target classes. We also investigate here the need to consider the number of EHR records, as part of control matching, and whether modeling separately for subgroups according to the number of EHR records is more effective. For each prediction task, we trained 4 different classifiers including 1-CNN, LSTM, Random Forest, and Logistic Regression, on data until the age of 40 or 50, and on several numbers of temporal variables. Using the number of EHR records for control matching was found crucial, and using learning models for subsets of the population according to the number of EHR records they have was found more effective. The deep learning models, particularly the 1-CNN, achieved the highest balanced accuracy and AUC scores in both male and female groups. In the male group, the highest results were also observed at age 50 with 100 temporal variables, resulting in a balanced accuracy of 90% and an AUC of 93%., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lama Abu Tahoun reports financial support was provided by Israeli Ministry of Science and Technology. The work was advised by advised by Prof. Moskovitch, in collaboration with data scientists and physicians from Maccabi Healthcare Services’s Center of data science in Healthcare, including Dr. Patalon, and experts in sleep medicine from Assuta’s Sleep Center, including Prof. Dagan, and Dr. Green. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Currently, pedestrians' road-crossing decisions depend on the traffic at the crossing point, crossing opportunities, and circumstantial elements. Longer wait times on the curb and time pressure raise the number of traffic violations among pedestrians. The era of fully autonomous vehicles (FAVs) promises new interactions. External Human-Machine Interfaces (eHMIs) aim to increase the understanding of FAVs' intentions and will influence pedestrians' intent to cross. Yet, how pedestrian behaviors will change in the FAV era remains unclear. Further, there are no good metrics for evaluating the intricate interaction of crossing-related factors., Methods: In a laboratory study, sixty participants observed crossing scenarios of a typical one-lane road with 10-12 FAVs driving along, two possible eHMI messages ("Cross!"/"Stop!"), and varying crossing opportunities (safe, risky, and unsafe). Participants had to indicate when they intended to cross the road using a designated button. Half of the participants were induced to feel time pressure. We developed index scores to convey the complexity of such crossing situations from the perspective of a pedestrian and used them to analyze the experimental data., Results: In total, 48% of participants' indications were to cross in safe crossing opportunities, 34% risky, and 18% unsafe; 69% were made when the eHMI proposition was "Cross!" and 31% for "Stop!". High, significant, and negative correlations were found for compatible responses, e.g., with a safe crossing gap and an eHMI sign to "Cross!". The opposite was true for incompatibility, e.g., a safe crossing gap and an eHMI sign to "Stop!" or an unsafe crossing gap and an eHMI sign to "Cross!". The time pressure group's median times to cross were shorter, making riskier decisions., Conclusion: Our findings reflect a tendency to comply with the eHMI. In more complex scenarios where the crossing opportunity was uncertain or waiting times were longer, we observed that pedestrians were more inclined to follow the eHMI's guidance to cross. These findings suggest that pedestrians may be more likely to follow the eHMI's suggestion to cross than their self-skill, especially under time pressure. Our indices and metrics reflect the intricate interaction aspects of pedestrian behavior with eHMIs.

Objectives: Evaluating the effectiveness and safety of repeated high-dose intradetrusor abobotulinumtoxin A (Dysport®) injections for the treatment of pediatric neurogenic bladders refractory to medications., Design: Retrospective interventional study., Participants: The cohort included 37 children (22 boys and 15 girls) of median age 9.2 years. Inclusion criteria were diagnosis of neurogenic bladder and failure to respond to medical treatment. Exclusion criteria were augmented bladder, insufficient data, and interval of > 11 months between video-urodynamic study and Dysport injection., Interventions: All participants were treated with an intra-detrusor injection of Dysport 30 IU/kg (up to 1000 IU) under general anesthesia. Repeated (second and third) injections were scheduled (6-12 months) in patients who demonstrated an improvement in cystometric parameters. All participants underwent video urodynamic testing before onset of treatment and 4-5 months after subsequent injection., Main Outcome Measures: Success of treatment was defined as a decrease in end filling pressure (EFP) to < 40 cm H 2 O and/or a 20% increase in maximal cystometric capacity (MCC). These parameters along with initial bladder features were evaluated for ability to predict treatment success., Results: No side effects of Dysport were observed or reported. The overall success rate was 62%. MCC increased by a median of 30% (IQR 200-300, p < 0.001), 37% (IQR 197-310, p = 0.001) and 45% (IQR 245-300, p = 0.025) after the first, second and third injections, respectively. Median EFP decreased from 45 cm H 2 O to 34 cm H 2 O (IQR 20-45, p = 0.029), 23 cm H 2 O (IQR 20-37, p = 0.004), and 20 cm H 2 O (IQR 12-32, p = 0.049) after the first, second, and third injections, respectively. No predicting factor of success of treatment were found; However, three of five cases of "end stage" bladder showed improvement., Conclusions: High-dose Dysport injection is safe and effective for the treatment of neurogenic bladder. Studies with larger cohort and a control group would further elucidate which bladders would benefit most. At present, we recommend treating also bladders with "end stage" features with botulinum toxin before considering augmentation., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Objective: To identify MRI findings that can indicate chronic physeal stress injury and differentiate it from acute Salter-Harris (SH) fracture of the pediatric knee or wrist., Methods: IRB-approved retrospective study of consecutively selected knee and wrist MRIs from 32 athletes with chronic physeal stress injury and 30 children with acute SH fracture. MRI characteristics (physeal patency, physeal thickening, physeal signal intensity (SI), continuity of the zone of provisional calcification (ZPC), integrity of the periosteum and/or perichondrium, pattern of periphyseal and soft tissue edema signal, and joint effusion) were compared., Results: Forty-eight chronic physeal stress injuries (mean age 13.1 years [8.2-17.5 years]) and 35 SH fractures (mean age 13.3 years [5.1-16.0 years]) were included. Any physeal thickening was more common with chronic stress injury (98% vs 77%, p = 0.003). Abnormal physeal SI was more common with SH fractures (91% vs 67%, p = 0.008). ZPC discontinuity strongly suggested chronic stress injury (79% vs 49%, p < 0.004). Periosteal and/or perichondrial elevation or rupture and soft tissue edema characterized most of the acute SH fractures (p < 0.001) and were seen only in 1 chronic stress injury (< 2%). While periphyseal edema was not significantly different in the two groups (p = 0.890), a joint effusion was associated with acute SH fracture (p < 0.001)., Conclusion: Chronic physeal stress injury of the pediatric knee and wrist shows higher incidence of ZPC discontinuity and focal physeal thickening compared to SH fracture, reflecting disruption in normal endochondral ossification. However, these findings can overlap in the 2 groups. Periosteal and/or perichondrial injury, soft tissue edema signal, and joint effusion strongly suggest SH fracture and are rarely present with chronic stress injury., (© 2024. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Introduction: This retrospective chart review aims to report a combined surgical approach of intraocular lens (IOL) fixation and gonioscopy-assisted transluminal trabeculotomy (GATT) for the treatment of subluxated IOLs and glaucoma or ocular hypertension., Methods: Charts of patients who underwent IOL fixation combined with GATT between November 2019 and July 2023 were reviewed. The main outcome measure was surgical success, defined as a well-centered IOL and an IOP of 18 mmHg or lower and either a 30% IOP reduction or a reduction in medications as compared to baseline. Complications and the need for reoperation were recorded., Results: Eleven patients who underwent GATT with IOL fixation were included. The mean age was 80.45 years (range: 73-90). IOL subluxation was associated with pseudoexfoliation in all cases. Seven patients underwent scleral fixation, and four underwent iris fixation. The mean follow-up was 15.36 (range: 2.7-26.6) months. The success rate was 72.73%. The mean baseline IOP was 20.63 ± 6.56 mmHg on 2.81 ± 1.53 medications. Four patients were on oral carbonic-anhydrase inhibitor (CAI) before surgery. The mean IOP at the end of the follow-up was 13.86 ± 3.5 mmHg on 1.36 ± 1.57 medications, and none were on oral CAIs. No intraoperative complications occurred, and transient hyphema and vitreous hemorrhage were the most common postoperative complications. All patients had a well-centered IOL. No patients needed additional surgery for IOL position or IOP control. The mean corrected distance visual acuity was 0.634 ± 0.62 logMAR at baseline and 0.36 ± 0.38 at the end of follow-up., Conclusions: GATT can be combined with IOL fixation to the sclera or iris to effectively reduce IOP and medication usage., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Iron deficiency (ID) without anemia is common in children with newly diagnosed celiac disease (CD). We aimed to assess the effect of iron supplementation versus no treatment on ferritin levels in newly diagnosed CD patients with ID adhering to a gluten-free diet (GFD). A retrospective review of children < 18 years, with low ferritin (≤ 10 ng/mL) and normal hemoglobin levels diagnosed between 12.2018 and 12.2021. We compared hemoglobin and ferritin levels between patients who received supplemental iron to those who did not. Data, including demographics, laboratory tests, and anthropometrics, were collected at baseline, and at 6 and 12 months following the initiation of the GFD. Adherence to GFD was assessed at each visit. Among 304 children diagnosed during the study period, 43 (14.1%) had iron deficiency anemia and 60 (19.7%) ID without anemia. Among children with ID, 29 (48%) were female, mean age 7.3 ± 3.9 years. Twenty-nine (48%) children received iron supplementation, and 31 (52%) did not. At the 12-month follow-up visit, tissue transglutaminase levels decreased significantly (p < 0.001), from a mean baseline level of 226.6 ± 47.8 to 34.5 ± 46 U/mL in children that received iron supplementation and from 234.2 ± 52.4 to 74.5 ± 88.7 U/mL in non-treated children, with no significant difference between the groups p = 0.22. Ferritin levels increased significantly (p < 0.001), from 9.0 ± 4.7 to 25.2 ± 20.8 ng/mL in patients who received supplementation and from 8.9 ± 3.8 to18.6 ± 9.5 ng/mL in patients who did not, with no significant difference between the groups (p = 0.46)., Conclusion: Most children with newly diagnosed celiac disease and iron deficiency, who adhere to GFD, will normalize ferritin levels within 12 months without the need of iron supplementation., What Is Known: • Iron deficiency and iron deficiency anemia are common in newly diagnosed celiac disease. • Improved iron absorption may follow mucosal healing process in patients adhering to a strict gluten-free diet., What Is New: • This single-center, retrospective cohort study evaluated the effect of iron supplementation versus no treatment on ferritin levels in children with newly diagnosed celiac disease with iron deficiency adhering to a gluten-free diet. • Most children with newly diagnosed celiac disease and iron deficiency, who adhere to gluten-free diet, will normalize ferritin levels within 12 months without the need of iron supplementation., (© 2024. The Author(s).)

Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We assessed real-life glycemic outcomes and predictors of composite measures of optimal glycemic control in children and adolescents with type 1 diabetes (T1D) during their initial 12 months of the MiniMed™ 780G use. Methods: This prospective observational multicenter study collected demographic, clinical, and 2-week 780G system data at five time points. Optimal glycemic control was defined as a composite glycemic control (CGC) score requiring the attainment of four recommended continuous glucose monitoring (CGM) targets, as well as the glycemia risk index (GRI) of hypoglycemia and hyperglycemia and composite CGM index (COGI). Outcome measures included longitudinal changes in multiple glycemic parameters and CGC, GRI, and COGI scores, as well as predictors of these optimal measures. Results: The cohort included 93 children, 43% girls, with a median age of 15.1 years (interquartile range [IQR] 12.9,17.0). A longitudinal analysis adjusted for age and socioeconomic index yielded a significant improvement in glycemic control for the entire cohort ( p time < 0.001) after the transition to 780G. The mean hemoglobin A1c (HbA1c) (SE) was 8.65% (0.12) at baseline and dropped by >1% after 1 year to 7.54% (0.14) ( p time < 0.001). Optimal glycemic control measures improved at 12 months post 780G; CGC improved by 5.6-fold ( P < 0.001) and was attained by 24% of the participants, the GRI score improved by 10-fold ( P = 0.009) and was achieved by 10% of them, and the COGI improved by 7.6-fold ( P < 0.001) and was attained by 20% of them. Lower baseline HbA1c levels and increased adherence to Advanced Hybrid Closed-Loop (AHCL) usage were predictors of achieving optimal glycemic control. Conclusions: The AHCL 780G system enhances glycemic control in children and adolescents with T1D, demonstrating improvements in HbA1c and CGM metrics, albeit most participants did not achieve optimal glycemic control. This highlights yet ongoing challenges in diabetes management, emphasizing the need for continued proactive efforts on the part of health care professionals, youth, and caregivers.

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project. Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age (FDR < 0.05, 40% of all LINE1 regions). This LINE1 pattern differed in magnitude across breeds of different sizes- the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species. Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of inter-species, demographic-dependent aging variation.

Hypergranulated wounds from thermal injury remain a complex and debilitating problem for burn patients. Currently, there is no standard therapy to prevent or treat hypergranulation following burn injury. Many centers use topical corticosteroids; however, their use seems to be geographically dependent and controversial. The primary aim of this study was to quantify the current use of topical corticosteroids for post-burn hypergranulation in North America (NA) and Europe, while secondarily assessing for perceptions of safety and efficacy. We designed a survey that was distributed to the members of the European and American Burn Associations. Data was extracted and analyzed using SPSS software. A total of 165 respondents completed the survey (90 and 75 for the European and NA members, respectively). Seventy-one of the 90 (78.9%) European respondents reported they routinely use topical steroids for suppression of hypergranulation tissue in burns, versus 25 of the 75 (33.3%) NA respondents (p<0.001). European respondents, compared to NA respondents, were significantly more likely to consider topical steroid use safe (100% vs. 74.4%, p <0.001) and effective (98.6% vs. 66.7%, p < 0.001) for treatment of hypergranulated burn wounds. There was no significant difference in reported systemic effects seen after topical steroid use when comparing NA respondents and European respondents (6.5% vs. 6.9%, p > 0.10). The results of this study suggest that the use of steroids for hypergranulation tissue in burn care is more prevalent in Europe than NA, which may be due to discordant views on safety and efficacy despite minimal reported adverse effects., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We report a versatile copper-catalyzed carbomagnesiation reaction of poly- and fully substituted 1-halocyclopropenyl esters. By fine-tuning the regioselectivity of the addition, we were able to access configurationally stable fully substituted cyclopropyl carbenoid intermediates. These intermediates were subsequently trapped with electrophiles to furnish stereodefined poly- and fully substituted halocyclopropyl esters. The regioselectivity of the addition was found to be dependent on the nature of the sp 2 substituents.

The empirical and clinical literature emphasizes the importance of alliance ruptures, signaling therapeutic processes occurring within and between the partners of the therapeutic dyad. However, knowledge about the underlying regulatory processes that occur amid ruptures is scarce. Identifying the underlying physiological markers may shed light on these regulatory processes. The overarching goal of the present study was to explore physiological markers of withdrawal and confrontation ruptures, within the patient and the therapist. Given the little known on the subject, we used a single-case design (94 episodic segments) to explore biologically based regulatory processes in the face of a rupture, contrasting confrontation ruptures versus withdrawal ruptures versus control episodes (emotional and neutral episodes). Findings showed that the patient and the therapist had contrasting physiological responses to the ruptures, depending on the type. During withdrawal ruptures, the patient exhibited high regulation, while the therapist did not show a clear physiological reaction. During confrontation ruptures, the patient exhibited low regulation, while the therapist exhibited high regulation. The different physiological regulation processes at times of ruptures suggest that, in withdrawal, the patient relied on intrapersonal regulation, contrasting with the interpersonal regulation observed in confrontation ruptures. Findings remained robust after controlling for speech turns and 10,000 Monte Carlo permutations to assess chance-level results. These findings provide initial evidence for the link between arousal and behavior in ruptures, offering valuable psychoeducational material for therapists to improve their handling of these challenging moments. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Ferritin, an iron storage protein and acute phase reactant, has been implicated in various aspects of human health and disease, including cancer. Previous studies have identified elevated serum ferritin (SF) levels in several cancer types, but a comprehensive examination across different malignancies remains lacking. This study aims to fill this gap by utilizing anonymized data from Maccabi Health Services (MHS), one of Israel's largest health organizations, to explore the association between elevated SF levels and the diagnosis of different malignancies., Methods: An extensive dataset from MHS, comprising 2.7 million members, including 1.3 million individuals who underwent SF level testing, was analyzed. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to assess the association between high SF levels and cancer diagnosis. Subgroup analysis was conducted to investigate variations across different malignancies., Results: The analysis revealed a significant association between elevated SF levels and cancer diagnosis among MHS members, with an OR of 1.9 (95% CI 1.71-2.15). Sub- group analysis unveiled differences in the association across malignancy types, with hematological, hepatobiliary and respiratory malignancies more strongly associated with high SF levels., Conclusions: This study provides further support for the link between elevated SF levels and malignancy, leveraging a vast dataset from MHS, underscoring potential utilities of elevated SF levels as a potential indicator for cancer with a variable role among different malignancy types., Impact: The identification of elevated SF levels as a potential indicator for underlying malignancy for seemingly-healthy individuals.

Background: Mental health (MH) conditions are prevalent in adolescents with childhood-onset SLE (cSLE). Early identification is crucial in preventing poor patient outcomes; however, MH screening rates remain low., Local Problem: From July 2021-January 2022, only 15% of adolescents in a paediatric tertiary care cSLE clinic were being screened for depression and anxiety. By November 2023, we aimed to increase the percentage of patients with cSLE (≥12-18 years) screened for depression (Patient Health Questionnaire: PHQ-9) and anxiety (Generalised Anxiety Disorder-7: GAD-7) from 15% to 80%., Methods: This quality improvement project employed the Model for Improvement framework. Stakeholders included the clinic team, patients and families, and MH providers. Statistical process control charts were used to analyse the outcome measure for percentage of screened patients with cSLE. Patient and caregiver satisfaction surveys were conducted at baseline and after screening as a balancing measure., Interventions: MH screening workflow with a referral algorithm was developed with stakeholders. Additional interventions included two MH training workshops for healthcare providers and a preclinic reminder of eligible patients for screening., Results: Over 21 months, 146 patients with cSLE completed 270 MH screens, increasing the screening rate from 15%, peaking at 100%, to a median of 56%. Sixty-six individuals (45%) reported symptoms of depression and/or anxiety on their initial screen. Of 270 screens, 44 individuals (17%) reported moderate to severe symptoms meeting the screening workflow criteria for referral to a MH service; 10% of patients screened were referred and seen by the MH service within 2-12 weeks. Patients and caregivers reported satisfaction with the MH screening process and quality of MH follow-up., Conclusion: Despite not sustainably meeting the target, MH screening rates increased in the cSLE clinic by nearly fourfold, demonstrating feasibility and acceptability. Patients expressed satisfaction with their mental health follow-up, emphasising its importance in their care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare the immediate and late complications associated with emergent cesarean sections (CS) performed during the first and second stages of active labor., Methods: We conducted a retrospective analysis of electronic medical records from a single academic center, including data from 577 patients who underwent emergent cesarean sections at 4 cm or more of cervical dilatation. Patients were divided into two groups: those who had CS during the first stage of labor (4-9 cm dilatation) and those who had CS at complete dilatation (10 cm). Maternal and neonatal outcomes were compared, including rates of complications such as uterine atony, post-partum hemorrhage, infection, and neonatal intensive care unit (NICU) admission., Results: Of the 577 patients, 352 underwent CS during active labor and 255 at complete dilatation. The complete dilatation group exhibited significantly higher rates of uterine atony (19.6% vs. 11.6%, p = 0.009) and uterine incision extension (34.2% vs. 16.5%, p = 0.0001). In addition, they had longer hospital stays (4.8 vs. 4.25 days, p = 0.003) and higher outpatient clinic visit rates (21.3% vs. 9.9%, p = 0.0001). Infection-related complications on readmission were more common in the complete dilatation group (20% vs. 9.7%, p = 0.001). Neonatal outcomes, including APGAR scores and NICU admissions, did not differ significantly between the groups., Conclusion: Emergent cesarean sections performed at complete cervical dilatation are associated with increased intra-operative and post-operative complications compared to those performed during active labor. These findings highlight the importance of considering the stage of labor when planning cesarean delivery to minimize risks and optimize outcomes for both mother and neonate., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) is designed to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing information, we were able to overcome the limitations inherent in breed-based estimates of genetic and physiological effects, and to probe the physiological and dietary basis of the age-related metabolome. We identified a significant effect of age on approximately 40% of measured metabolites. Among other insights, we discovered a potentially novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which can only be generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the higher ptmAA levels in older dogs. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

Background: For three decades, fractional ablative CO 2 lasers have been used for skin rejuvenation. With breakthroughs in laser technology and expanding popularity, new recommendations and suggestions arise on a regular basis., Objective: To develop up-to-date clinical recommendations on safety measures, therapeutic framework, and techniques to improve treatment outcomes., Methods: Using Google Forms, a questionnaire with 188 questions was given to a varied sample of 21 dermatologists and plastic surgeons from various countries and practice contexts. A second questionnaire with 11 items was created to resolve any gaps or discrepancies., Results: Active face infections are considered a treatment contraindication by 95% of panelists. Burns, recent sun exposure, and pregnancy or breastfeeding were also considered contraindications (according to 67% of panelists). Over 90% employ bacterial and viral prophylaxis, however the majority (67%) do not prescribe antifungal prophylaxis. The most often stated anesthetic treatments by panelists are topical anesthetic cream, nerve blocks, and oral analgesics (according to 95%, 81%, and 62% of panelists respectively). Over 90% of panel members suggested treatment setting alterations for individuals with Fitzpatrick skin types III-IV. Following reepithelization, which happens between 8 and 42 days after the treatment, the majority (76%) of panelists advocate continuing standard skin care routines including active ingredients. Eighty-one percent of panelists recommend using supplementary treatment to maximize results. Supplementary treatment recommendations included use of neuromodulators (76% of panelists), Intense Pulsed Light Therapy treatments pre and postprocedure (61% of panelists), and injection-based therapies such as (Hyaluronic Acid fillers, and biostimulatory fillers) (recommended by 48% of panelists). 60% of panelists perform FACL to improve skin laxity treatment in nonfacial areas and adjust their settings accordingly., Limitations: Our results reflect only a modest panel size; with a focus on a specific device. Although experienced, the small number of panelists, recommendations, and personal adverse reactions encounters for resurfacing indication, might be biased., Conclusion: Fractional CO 2 laser is a popular and effective skin rejuvenation treatment with minimal downtime and side effects. This study presents new therapy recommendations to resolve treatment uncertainty and provide complete care suggestions for best results., (© 2024 The Author(s). Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

We report observations of discrete charge states of a coherent two-level system (TLS) that is strongly coupled to an offset-charge-sensitive superconducting transmon qubit. We measure an offset charge of 0.072e associated with the two TLS eigenstates, which have a transition frequency of 2.9 GHz and a relaxation time exceeding 3 ms. Combining measurements in the strong dispersive and resonant regime, we quantify both transverse and longitudinal coupling of the TLS-qubit interaction. We further perform joint tracking of TLS transitions and quasiparticle tunneling dynamics but find no intrinsic correlations. This Letter demonstrates microwave-frequency TLS as a source of low-frequency charge noise.

Objective: To evaluate the long-term safety of controlled ovarian stimulation for fertility preservation prior to breast cancer chemotherapy treatment DESIGN: Retrospective observational cohort SUBJECTS: 213 women aged 18-43 years with newly diagnosed stage I-III breast cancer treated with systemic chemotherapy during 2015-2019. Of those, 74 underwent controlled ovarian stimulation for fertility preservation recipients and 141 did not (controls)., Exposure: Controlled ovarian stimulation for fertility preservation MAIN OUTCOME MEASURES: Invasive disease-free survival, calculated from the time of surgery to the time of detection of breast cancer recurrence or death, whichever came first., Results: At diagnosis, fertility preservation recipients were significantly younger than controls (32.7 vs 38.5 years), were less likely to be partnered (44.4% vs 90.1%) or parous (38.9% vs 95%) and were more likely to harbor a BRCA germline mutation (36.5% vs 14.2%). Disease characteristics and treatment modalities were comparable between groups, apart from tumor staging, with maximal tumor diameter being over 5 cm in 22.2% of fertility preservation recipients as opposed to 5.7% of controls (P<0.05). Mean follow-up was 60.9 and 65.4 months for fertility preservation recipients and controls, respectively. 5-year-invasive disease free survival was 80% for fertility preservation recipients and 86% for controls (p=0.20). In a multivariate analysis adjusted for statistically significant covariates, invasive disease free survival remained similar between the groups (Hazards Ratio (HR), 0.86, 95CI 0.4-1.87, p = 0.71). Invasive disease free survival rates were not statistically different in clinically relevant subgroups including patients receiving neoadjuvant chemotherapy (HR 1.57, CI 95 0.62-3.99, p=0.34), and those co-treated with tamoxifen during stimulation due to an ER-positive disease (HR 1.66, 95CI 0.67-3.49, p=0.23)., Conclusions: Fertility preservation with controlled ovarian stimulation for patients with breast cancer was not found to impair long-term oncologic outcomes, including in emerging clinically relevant subgroups., (Copyright © 2024. Published by Elsevier Inc.)

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ-producing bacteria was sufficient to drive systemic tumor antigen-specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3 - CD4 + and CD8 + T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ-producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.

Aim: To compare clinical outcomes using short and long co-incubation protocols in sibling oocytes based on embryo morphokinetic outcomes measured by time-lapse incubator with stratification based on a woman's age and sperm quality., Design: Our study included 72 cycles with >6 oocytes retrieved. Sibling oocytes were distributed for two parallel protocols: short (3 h; n = 421) or long (16-20 h; n = 434) insemination, using the same amount of spermatozoa from the same prepared sample. Oocytes were then washed and incubated for 5 days. Time-lapse annotations of embryos were performed by experienced embryologists and artificial intelligence-based Known Implantation Data scores for day 3 and day 5 were calculated with EmbryoScope software., Results: Short-insemination group exhibited a higher blastulation rate, better morphokinetic indicators, and higher Known Implantation Data scores on day 3 and day 5 of the utilized embryos. However, the fertilization rate and clinical pregnancy rate per embryo transfer did not differ between experimental groups. A higher rate of abnormal fertilization (>2 pronuclei) after long insemination was recorded in women under 35 years old or with a total motile sperm count above 5 million and above 40% motility after preparation. A higher rate of usable embryos was observed after short insemination with a total motile sperm count above 30 million before preparation or 5 million and over 40% motility after preparation., Conclusions: Our results suggest that a short insemination protocol results in better embryo quality and should be considered as a favorable protocol, especially in young female patients or male patients with high sperm quality., (© 2024 American Society of Andrology and European Academy of Andrology.)

Unlabelled: Knowledge has become more open and accessible to a large audience with the "democratization of information" facilitated by technology. This paper provides a sociohistorical perspective for the theme issue "Responsible Design, Integration, and Use of Generative AI in Mental Health." It evaluates ethical considerations in using generative artificial intelligence (GenAI) for the democratization of mental health knowledge and practice. It explores the historical context of democratizing information, transitioning from restricted access to widespread availability due to the internet, open-source movements, and most recently, GenAI technologies such as large language models. The paper highlights why GenAI technologies represent a new phase in the democratization movement, offering unparalleled access to highly advanced technology as well as information. In the realm of mental health, this requires delicate and nuanced ethical deliberation. Including GenAI in mental health may allow, among other things, improved accessibility to mental health care, personalized responses, and conceptual flexibility, and could facilitate a flattening of traditional hierarchies between health care providers and patients. At the same time, it also entails significant risks and challenges that must be carefully addressed. To navigate these complexities, the paper proposes a strategic questionnaire for assessing artificial intelligence-based mental health applications. This tool evaluates both the benefits and the risks, emphasizing the need for a balanced and ethical approach to GenAI integration in mental health. The paper calls for a cautious yet positive approach to GenAI in mental health, advocating for the active engagement of mental health professionals in guiding GenAI development. It emphasizes the importance of ensuring that GenAI advancements are not only technologically sound but also ethically grounded and patient-centered., (© Zohar Elyoseph, Tamar Gur, Yuval Haber, Tomer Simon, Tal Angert, Yuval Navon, Amir Tal, Oren Asman. Originally published in JMIR Mental Health (https://mental.jmir.org).)

A 65-year-old woman was admitted to the neurology department with a suspected demyelinating disease due to complaints of progressive pain and weakness in both upper and lower limbs, as well as urinary incontinence. MRI of the spine revealed complex disc osteophyte with compression of the spinal cord in the cervical and lumbar spine at several vertebral levels, and localized enhancement in the cervical spine at the site of maximal spinal canal stenosis. During her hospitalization, the patient underwent extensive evaluation to rule out any systematic inflammatory diseases, infections, and malignancy. Chest CT revealed bilateral mediastinal lymphadenopathy. Transbronchial mediastinal lymph node biopsy showed numerous non-necrotizing granulomas without evidence of malignancy. After a thorough and careful exclusion of a demyelinating, infectious, and paraneoplastic myelopathies, and based on clinical, radiographic, and pathological findings, the patient was diagnosed with both neurosarcoidosis and spondylotic myelopathy. She was then treated for neurosarcoidosis, including glucocorticosteroids, azathioprine, and a biosimilar of the anti-TNF alpha agent infliximab, resulting in both clinical and radiographic improvement. Intramedullary spinal neurosarcoidosis is very rare and may present with clinical features of spondylotic myelopathy, with typical imaging findings occurring only in areas of spinal canal stenosis.

Evolution often follows similar trajectories in replicate populations, suggesting that it may be predictable. However, populations are naturally embedded in multispecies communities, and the extent to which evolution is contingent on the specific species interacting with the focal population is still largely unexplored. Here, we study adaptations in strains of 11 different species, experimentally evolved both in isolation and in various pairwise co-cultures. Although partner-specific effects are detectable, evolution was mostly shared between strains evolved with different partners; similar changes occurred in strains' growth abilities, in community properties, and in about half of the repeatedly mutated genes. This pattern persisted even in species pre-adapted to the abiotic conditions. These findings indicate that evolution may not always depend strongly on the biotic environment, making predictions regarding coevolutionary dynamics less challenging than previously thought. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo 1,2 . With emerging evidence that bacteria naturally home in on tumours 3,4 and modulate antitumour immunity 5,6 , one promising application is the development of bacterial vectors as precision cancer vaccines 2,7 . Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4 + and CD8 + T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity., (© 2024. The Author(s).)

Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments., Competing Interests: YI is the founder of Oberon Sciences. The authors report no conflicts of interest in this work., (© 2024 Sigawi et al.)

Background: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available., Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study., Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years., Conclusion: Ongoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

Background: Nirmatrelvir-ritonavir was granted emergency use authorization in Israel in January 2022 to treat high-risk patients with mild-to-moderate COVID-19. The aim of the study was to assess the association between nirmatrelvir-ritonavir treatment and COVID-19-related hospitalization and healthcare resource utilization (HCRU) in a country with a high level of vaccinations compared to patients who were offered treatment and declined. Methods: The Maccabi Healthcare Services dataset was used to identify high-risk SARS-CoV-2-positive adults from January to February 2022 who received nirmatrelvir-ritonavir within 5 days of symptom onset (treatment group) or who were offered nirmatrelvir-ritonavir treatment and declined it (reference group). COVID-19-related hospitalizations and all-cause mortality and HCRU within 30 days were compared between treatment and reference groups using inverse probability of treatment weighting. Results: Treatment and reference groups included 3460 (median age, 68.4 years) and 1654 (70.2 years) patients, respectively. Patients with ≥1 dose of COVID-19 vaccine accounted for 89.5% (treatment group) and 72.1% (reference group) of the total. Treatment was associated with a lower risk of COVID-19-related hospitalization (adjusted OR, 0.59 [95% CI, 0.41,0.83]). Results were similar by age group (18-64/≥65 years) and among patients with/without vaccination in the prior 180 days. There were 11 (0.3%) versus 11 (0.7%) deaths in the treatment and reference groups, respectively. Treated patients had lower inpatient HCRU and greater less intensive outpatient HCRU (e.g., telemedicine and emergency room visits). Conclusions: Nirmatrelvir-ritonavir treatment was associated with a reduced risk of COVID-19-related hospitalization and a shift to less intensive outpatient HCRU. Comparison with a reference group of nirmatrelvir-ritonavir-eligible patients who declined treatment enabled an unbiased outcome assessment. Real-world data gathered during the Omicron BA.1 variant wave of COVID-19 in Israel support the continued use of nirmatrelvir-ritonavir for high-risk adults of all ages, regardless of previous vaccinations.

The Eastern Mediterranean Sea (EMS) exhibits high temperature and salinity, low levels of biologic production and is considered oligotrophic. Nonetheless, it is also a hotspot of biodiversity, with several important endangered flagship species, including several species of sea turtles. These turtles serve as bioindicators for the health of their ecologic systems, due to changes in diet, habitat and migration patterns that characterize different stages in their lives. This study covered 100 blood samples taken between 2008 and 2019 from 72 green sea turtles (Chelonia mydas) tested for 67 elements, some of which carry toxic potential. The turtles were treated at the Israeli Sea Turtle Rescue Center (ISTRC) after being rescued from sea, exhibiting a variety of health conditions and Injuries. The data were compared to similar studies worldwide and serve as a basis for monitoring the health status of the green sea turtles' EMS populations. The results of all animals presented noticeably high levels of sulfur - an order of magnitude higher than sea turtles from other locations around the world. This paper discusses the possible origins of this element, as well as its potential effects, while raising the question regarding the ability of these sea turtles to endure such sulfur levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Plastics are an indispensable part of modern life. Due to the harmful environmental consequences of petroleum-based plastic usage, there is an urgent need to replace them with biodegradable bioplastics that meet the sustainability standards required for a low environmental footprint. Here, we use plant-derived proteins to produce bioplastics. Since most plant-derived proteins are not water-soluble, there has always been a need to use acidic or basic solutions or organic solvents with plasticizers and crosslinkers to produce bioplastic. Here, we present a counterintuitive approach for using water-insoluble plant-derived soy and pea proteins to manufacture large-scale bioplastics using only water as a solvent without common plasticizers or crosslinkers. We show that bioplastics can form via a self-assembly process initiated by a small molecular initiator while maintaining favourable mechanical properties. The lack of crosslinking and the protein nature of the bioplastic leads to a rapid biodegradation process under various conditions. Overall, the approach we present is highly attractive in terms of cost and time, and most importantly, it obeys all the relevant principles of green chemistry in bioplastics production., (© 2024 Wiley‐VCH GmbH.)

Objective: Contrast-enhanced imaging, including magnetic resonance imaging and, more recently, contrast-enhanced digital mammography (CEM), is indicated for the precise diagnosis of invasive lobular carcinoma (ILC). The aim of our study was to further validate the use of CEM for evaluation of extent of disease in ILC cases, with digital breast tomosynthesis (DBT) as an adjunct., Methods: A retrospective, institutional review board approved study was conducted in a tertiary medical center. All CEM examinations performed on ILC patients between 2017 and 2023 were reread by 2 dedicated breast radiologists. Clinical data and pathology reports were retrieved from electronic medical records. The longest diameter of the enhancing lesion was correlated to pathology findings. In addition, for each case, the readers provided brief commentary on the added value of DBT., Results: Twenty-four CEM examinations were evaluated. The subjects in the study cohort were on average older than expected for ILC patients (74 vs 63 years) and were unable to undergo breast magnetic resonance imaging due to advanced age and comorbidities. Three subjects were treated with neoadjuvant therapy and thus were excluded from the correlation to pathology analysis. Enhancing lesions, ranging from 4-75 mm, strongly correlated to pathology results, with statistical significance. This was demonstrated for mass and nonmass lesions (r = 0.94, P < 0.001 and r = 0.99, P = 0.002, respectively). For most lesions (17/24, 71%), readers remarked that the addition of DBT allowed for improved characterization of lesion margins, mainly detecting architectural distortion., Conclusions: When compared with the pathology findings, ILC was accurately diagnosed and assessed using CEM. The addition of DBT was reported by the interpreting radiologists as a valuable adjunct for margin analysis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Robust and convenient risk stratification of patients with paediatric and adult congenital heart disease (CHD) is lacking. This study aims to address this gap with an artificial intelligence-enhanced electrocardiogram (ECG) tool across the lifespan of a large, diverse cohort with CHD., Methods: A convolutional neural network was trained (50%) and tested (50%) on ECGs obtained in cardiology clinic at the Boston Children's Hospital to detect 5-year mortality. Temporal validation on a contemporary cohort was performed. Model performance was evaluated using the area under the receiver operating characteristic and precision-recall curves., Results: The training and test cohorts composed of 112 804 ECGs (39 784 patients; ECG age range 0-85 years; 4.9% 5-year mortality) and 112 575 ECGs (39 784 patients; ECG age range 0-92 years; 4.6% 5-year mortality from ECG), respectively. Model performance (area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.77-0.81; area under the precision-recall curve 0.17, 95% confidence interval 0.15-0.19) outperformed age at ECG, QRS duration, and left ventricular ejection fraction and was similar during temporal validation. In subgroup analysis, artificial intelligence-enhanced ECG outperformed left ventricular ejection fraction across a wide range of CHD lesions. Kaplan-Meier analysis demonstrates predictive value for longer-term mortality in the overall cohort and for lesion subgroups. In the overall cohort, precordial lead QRS complexes were most salient with high-risk features including wide and low-amplitude QRS complexes. Lesion-specific high-risk features such as QRS fragmentation in tetralogy of Fallot were identified., Conclusions: This temporally validated model shows promise to inexpensively risk-stratify individuals with CHD across the lifespan, which may inform the timing of imaging/interventions and facilitate improved access to care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Neurogenic thoracic outlet syndrome (NTOS) is a dynamic compression of the brachial plexus. This study aimed to evaluate the correlation between the concave deformity of the posterior edge of the anterior scalene muscle (CDAS) on sagittal T1 with intraoperative findings of vascular compression. The second aim was to define the NTOS vascular subtypes and establish possible treatments., Methods: We retrospectively reviewed patients who met the Consortium for Research and Education on Thoracic Outlet Syndrome criteria for NTOS and were operated on after a failed rehabilitation program., Results: Forty-four patients were included; mean age was 29.51 years (range: 13-55 years), and 24 (54.5%) were women. CDAS on sagittal T1 magnetic resonance imaging (MRI) was identified in 20 of 44. Patients were divided into two categories: type A (pure NTOS) (20 of 44); and type B (mixed neurogenic-vascular variants) (24 of 44). Type B was divided into B1, B2, and B3, corresponding to subclavian artery (SCA) compression (seven of 44), subclavian vein compression (SCV) (five of 44), and both SCA and SCV compression (12 of 44), respectively. All patients with B1 had CDAS on MRI T1 sagittal, whereas CDAS was found on 5%, 60%, and 58.3% in types A, B2, and B3, respectively. Intraoperatively, all patients had at least one structural anomaly. Preoperative symptoms of lower or middle-lower brachial plexus trunk compressions were more prominent in patients with the vascular variant (B1: 85%, B2: 83%, and B3: 83%) than the pure NTOS (type A) (40%)., Conclusions: NTOS presents as four subtypes: pure neurogenic (A) and vascular (B1, B2, and B3). Preoperative middle/lower trunk symptoms combined with positive upper limb duplex ultrasound of the SCA, SCV, and sagittal MRI show that a CDAS is correlated with the vascular form of NTOS and predicts failure of preoperative rehabilitation program., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Droplet-based microfluidic systems have received much attention as promising tools for fabricating monodisperse microspheres of alginate solutions with high accuracy and reproducibility. The immediate and simple ionotropic gelation of alginate, its biocompatibility, and its tunability of mechanical properties make it a favorable hydrogel in the biomedical and tissue engineering fields. In these fields, micron-sized alginate hydrogel spheres have shown high potential as cell vehicles and drug delivery systems. Although on-chip microfluidic gelation of the produced alginate droplets is common, several challenges remain. Complicated chemical and microfabrication processes are required, and the risk of microchannel clogging is high. In the current study, we present an easy-to-use microfluidic external gelation process to produce highly spherical and monodisperse microspheres from very low-concentrated alginate-RGD solution [0.5% (w/v)]. To accomplish this, gelatin, a thermo-sensitive and inexpensive biomaterial, was incorporated into the alginate solution as a sacrificial biomaterial that mediates the off-chip external gelation of the alginate with Ca 2+ , and avoids droplet coalescence. Utilizing the methodology mentioned above, we successfully generated monodisperse alginate microspheres (AMs) with diameters ranging from 27 μm to 46 μm, with a coefficient of variation of 0.14, from a mixture of Arg-Gly-Asp (RGD)-modified very low viscosity alginate and gelatin. These RGD-AMs were used as microcarriers for human umbilical vein endothelial cells. The described easy-to-use and cost-effective microfluidic off-chip external gelation strategy exhibits comparable advantages to on-chip external gelation and demonstrates superiority over the latter since clogging is impossible., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The digital divide, particularly within the context of Artificial Intelligence (AI) sport podcasts, presents significant behavioral and psychosocial challenges for student engagement. This study examines the disparities in access to and proficiency with Information Communication Technologies (ICTs) across different demographic groups, focusing on gender, age, and religious level. The advent of the commercial web has heightened the significance of these divides, as the first-level digital divide concerns access to the internet, while the second-level digital divide pertains to the ability to use technology proficiently. The existing literature has consistently highlighted persistent inequalities in these areas, which significantly impact the extent to which students from various backgrounds can engage with AI sport podcasts effectively. Understanding these dynamics is crucial for developing strategies to bridge the gap and ensure equitable access to digital learning resources.

Background: Histological evaluation of ovarian tissue harvested as part of the attempt to preserve fertility might clarify the mechanism by which ovarian failure is caused. The purpose of this study was to compare the histologic appearance of ovarian tissue harvested for ovarian tissue cryopreservation (OTC) in chemotherapy naïve and chemotherapy exposed patients regarding the presence of follicles in different stages of development and to explore ovarian tissue histology in patients exposed to low- and high-cytotoxicity risk chemotherapy., Methods: A cohort of post-pubertal cancer survivors who underwent OTC between 1997 and 2018 was evaluated. An expert pathologist reviewed the pathology slides taken during OTC. The assessment included counting number of primordial, primary, secondary, and antral follicles. A comparison was made between chemotherapy naïve and chemotherapy exposed women and further between women who previously received low- versus high-risk gonadotoxic regimens., Results: Seventy post-pubertal patients were included in the study. Seventeen (24.3%) received chemotherapy prior to OTC, and 53 (75.7%) were chemotherapy naïve at the time of OTC. A significant difference was found only in the number of secondary follicles, which was increased in chemotherapy naïve patients (2.81±4.26 vs. 0.88±1.18, respectively; P=0.005). Similar results were observed in a subgroup analysis of hematologic malignancies separately. Comparison of patients with previous exposure to chemotherapy revealed similar follicular appearance, except for the number of secondary follicles, which was higher in patients receiving low-risk compared to high-risk chemotherapy (1.40±1.28 vs. 0.14±0.35, respectively; P=0.006)., Conclusions: The ovarian follicular pool at OTC appears comparable between chemotherapy naïve individuals and those post-exposure, as well as among patients receiving low versus high-risk gonadotoxic regimens, with the exception of secondary follicles, which are presented in increased numbers in chemotherapy naïve and those exposed to low-risk gonadotoxic chemotherapy.

NKG2D is a central activating receptor involved in target recognition and killing by Natural Killer and CD8 + T cells. The known role of NKG2D is to recognize a family of self-induced stress ligands that are upregulated on stressed cells such as cancerous or virally infected cells. Fungal pathogens are a major threat to human health, infecting more than a billion patients yearly and becoming more common and drug resistant. Here we show that NKG2D plays a critical role in the immune response against fungal infections. NKG2D can recognize fungal pathogens from most major families including Candida, Cryptococcus and Aspergillus species, and mice lacking NKG2D are extremely sensitive to fungal infections in models of both invasive and mucosal infections, making NKG2D an anti-fungal pattern recognition receptor., (© 2024. The Author(s).)

The MiniMUGA genotyping array is a popular tool for genetic quality control of laboratory mice and genotyping samples from most experimental crosses involving laboratory strains, particularly for reduced complexity crosses. The content of the production version of the MiniMUGA array is fixed; however, there is the opportunity to improve the array's performance and the associated report's usefulness by leveraging thousands of samples genotyped since the initial description of MiniMUGA. Here, we report our efforts to update and improve marker annotation, increase the number and the reliability of the consensus genotypes for classical inbred strains and substrains, and increase the number of constructs reliably detected with MiniMUGA. In addition, we have implemented key changes in the informatics pipeline to identify and quantify the contribution of specific genetic backgrounds to the makeup of a given sample, remove arbitrary thresholds, include the Y Chromosome and mitochondrial genome in the ideogram, and improve robust detection of the presence of commercially available substrains based on diagnostic alleles. Finally, we have updated the layout of the report to simplify the interpretation and completeness of the analysis and added a section summarizing the ideogram in table format. These changes will be of general interest to the mouse research community and will be instrumental in our goal of improving the rigor and reproducibility of mouse-based biomedical research., Competing Interests: Conflicts of interest The authors have no conflict of interest to declare. None of the authors have a financial relationship with Neogen Inc. apart from the service contracts listed above., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)