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Purpose: This research aimed to evaluate evidence of Pathways parent-mediated early autism intervention as a culturally and linguistically sensitive intervention (CLSI) for Hispanic families with autistic children. Methods: We used Bernal et al.'s ecologically valid (EV) framework to evaluate current practice and Hispanic parents' perceptions of Pathways 1 ½ years after completing the intervention. Both quantitative and qualitative methods were used. Nineteen parents were contacted, of which 11 completed a semi-structured interview about their experience with Pathways. Results: On average, the group that completed the interview was less educated, had more monolingual Spanish speakers, and rated their general experience with the intervention slightly more positively than those who did not agree to complete the interview. A review of Pathways's current practices through the lens of the EV framework suggested that Pathways was a CLSI for Hispanic participants in the domains of context, methods, language, and persons. Parental interviews echoed these strengths. However, Pathways did less well balancing evidence-based intervention strategies for autistic children with the heritage value of "respeto." Conclusion: Pathways demonstrated strengths regarding cultural and linguistic sensitivity for Hispanic families with young autistic children. Future work with our community stakeholder group will integrate heritage and majority culture perspectives to strengthen Pathways as a CLSI.

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

Despite the noted risks of sport specialization, it is evident that parents, athletes, and coaches are engaging in and promoting early sport specialization. To develop more effective intervention strategies, researchers and other stakeholders should consider evaluating this behavior through a multilevel theoretical perspective and comprehensively evaluating the levels of influence. In response to recent calls for ecological assessments and a need for more theory-based research, we have created an ecological framework for youth sport based on the information synthesized in this literature review. To this end, the use of a social ecological perspective may help to better inform youth sport specialization research. The literature supports the multi-factorial determinants of behavior and the interplay between each of the levels of influence is important. Keywords: Youth Sports; Sport Specialization; Social Ecological Model, Early sport specialization is a concept that has grown more popular in youth and adolescent sports over the last several years. Sport specialization occurs for many reasons, primarily focused on [...]

Abstract Cell surface scavenger receptors contribute to homoeostasis and the response to pathogens and products associated with damage by binding to common molecular features on a wide range of targets. Apoptosis inhibitor of macrophage (AIM/CD5L) is a soluble protein belonging to the scavenger receptor cysteine-rich (SRCR) superfamily that contributes to prevention of a wide range of diseases associated with infection, inflammation, and cancer. AIM forms complexes with IgM pentamers which helps maintain high-levels of circulating AIM in serum for subsequent activation on release from the complex. The structural basis for AIM recognition of IgM as well as other binding targets is unknown. Here we apply cryogenic electron microscopy imaging (cryo-EM) to show how interfaces on both of AIM’s C-terminal SRCR domains interact with the Fcμ constant region and J chain components of the IgM core. Both SRCR interfaces are also shown to contribute interactions important for AIM binding to damage-associated molecular patterns (DAMPs).

Abstract Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

Abstract Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

Abstract DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.

Abstract The mental health impacts of climate change are increasingly documented; however, less research has investigated the relationship between climate change-related psychological distress and engagement with the issue. The results from two national probability samples of U.S. adults show that 16% report at least one feature of climate change psychological distress and that certain groups have higher levels of distress than others (e.g., Hispanic/Latinos, lower income adults, younger adults). Importantly, people experiencing distress are more likely to engage in collective action on climate change or express a willingness to do so, even when controlling for several correlates of environmental behavior (e.g., political ideology, collective efficacy beliefs). These findings highlight that many Americans are experiencing psychological distress from climate change, and those who do are more involved in collective climate action. People experiencing such distress may benefit from resources to support mental health and engagement with climate change.

Abstract Background For decades, Israel’s economic policy has favored either outsourcing or privatization of public services, including healthcare, generating an ongoing and prolonged debate of this approach. In 1997 school health services (SHS) for elementary and middle school pupils was outsourced to a sub-contractor firm, reducing budget, but also standards, for nurses and physicians. Consequently, the service has dwindled and was focused more and more on vaccinations. Between 2007 and 2012, under full private contractor delivery, SHS quality diminished substantially, leading to a significant decline in vaccination coverage in the Southern District. In 2012, a decision was made to return SHS to state control. Methods This study analyzes the delivery parameters of SHS between the period when the service was operated by a private contractor from 2011to 2/2012, and the subsequent provision of the service directly by Ministry of Health (MoH) between 3/2012 and 2013. We compared the rates of vaccination coverage, screening tests and health education programs. Results A statistically significant increase in SHS delivery for vaccinations and screening was observed in the Southern District of MoH after the transfer of service from contractor. The increase was variable in different population subgroups, and especially notable in the Bedouin schools of the District, where the MMRV vaccination rose from 19.3% to 96.8%. However, a substantial and significant reduction in health education activities was also noted, overall from 24.9% to 5.0%. Conclusions The findings suggest that substantial benefits can be derived from direct provision of SHS by MoH and its regional offices, especially in the areas of reduced accessibility and lower socio-economic status. The case study of SHS in the Southern District of Israel can serve as an important example highlighting the impacts of privatization vs nationalization, with potential implications in other fields. These insights should be integral to future discussions of healthcare service provision.

Abstract Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

Abstract The response of the ocean overturning circulation to global warming remains controversial. Here, we integrate a multiproxy record from International Ocean Discovery Program Site U1490 in the western equatorial Pacific with published data from the Pacific, Southern and Indian Oceans to investigate the evolution of deep water circulation during the Miocene Climate Optimum (MCO) and Middle Miocene Climate Transition (MMCT). We find that the northward export of southern-sourced deep waters was closely tied to high-latitude climate and Antarctic ice cover variations. Global warming during the MCO drove a progressive decrease in carbonate ion concentration and density stratification, shifting the overturning from intermediate to deeper waters. In the western equatorial Pacific, carbonate dissolution was compensated by increased pelagic productivity, resulting in overall elevated carbonate accumulation rates after ~16 Ma. Stepwise global cooling and Antarctic glacial expansion during the MMCT promoted a gradual improvement in carbonate preservation and the initiation of a near-modern Pacific overturning circulation. We infer that changes in the latitudinal thermal gradient and in Southern Ocean zonal wind stress and upper ocean stratification drove radically different modes of deep water formation and overturning across the MCO and MMCT.

Biocatalysis has established itself as a successful tool in organic synthesis. A particularly fast technique for screening enzymes is the in vitro expression or cell-free protein synthesis (CFPS). The system is based on the transcription and translation machinery of an extract-donating organism to which substrates such as nucleotides and amino acids, as well as energy molecules, salts, buffer, etc., are added. After successful protein synthesis, further substrates can be added for an enzyme activity assay. Although mimicking of cell-like conditions is an approach for optimization, the physical and chemical properties of CFPS are not well described yet. To date, standard conditions have mainly been used for CFPS, with little systematic testing of whether conditions closer to intracellular conditions in terms of viscosity, macromolecules, inorganic ions, osmolarity, or water content are advantageous. Also, very few non-physiological conditions have been tested to date that would expand the parameter space in which CFPS can be performed. In this study, the properties of an Escherichia coli extract-based CFPS system are evaluated, and the parameter space is extended to high viscosities, concentrations of inorganic ion and osmolarity using ten different technical additives including organic solvents, polymers, and salts. It is shown that the synthesis of two model proteins, namely superfolder GFP (sfGFP) and the enzyme truncated human cyclic GMP-AMP synthase fused to sfGFP (thscGAS-sfGFP), is very robust against most of the tested additives.

Abstract Digital Breast Tomosynthesis (DBT) has revolutionized more traditional breast imaging through its three-dimensional (3D) visualization capability that significantly enhances lesion discernibility, reduces tissue overlap, and improves diagnostic precision as compared to conventional two-dimensional (2D) mammography. In this study, we propose an advanced Computer-Aided Detection (CAD) system that harnesses the power of vision transformers to augment DBT’s diagnostic efficiency. This scheme uses a neural network to glean attributes from the 2D slices of DBT followed by post-processing that considers features from neighboring slices to categorize the entire 3D scan. By leveraging a transfer learning technique, we trained and validated our CAD framework on a unique dataset consisting of 3,831 DBT scans and subsequently tested it on 685 scans. Of the architectures tested, the Swin Transformer outperformed the ResNet101 and vanilla Vision Transformer. It achieved an impressive AUC score of 0.934 ± 0.026 at a resolution of 384 $$\times$$ × 384. Increasing the image resolution from 224 to 384 not only maintained vital image attributes but also led to a marked improvement in performance (p-value = 0.0003). The Mean Teacher algorithm, a semi-supervised method using both labeled and unlabeled DBT slices, showed no significant improvement over the supervised approach. Comprehensive analyses across different lesion types, sizes, and patient ages revealed consistent performance. The integration of attention mechanisms yielded a visual narrative of the model’s decision-making process that highlighted the prioritized regions during assessments. These findings should significantly propel the methodologies employed in DBT image analysis by setting a new benchmark for breast cancer diagnostic precision.

Abstract Background Alcohol use disorder (AUD) poses a significant global health challenge. Traditional management strategies often face high relapse rates, leading to a need for innovative approaches. Mindfulness-based relapse prevention (MBRP) has emerged as a promising intervention to enhance cognitive control, reduce cue-related craving and improve interoceptive processing. Neuroimaging studies suggest that mindfulness training can modulate brain networks associated with these factors, potentially improving treatment outcomes for AUD. Neuroimaging studies suggest that mindfulness training can modulate brain networks linked to these brain functions, potentially improving treatment outcomes for AUD. However, it is unclear how MBRP links to neurophysiological measures such as frontal midline theta oscillations (FMΘ) and whether the beneficial effects of MBRP can be increased by enhancing FMΘ. Here, we will use two different forms of neuromodulation to target and enhance these oscillations, and evaluate their impact on the effectiveness of MBRP. Methods This study will employ a four-arm randomized controlled trial to evaluate the synergistic effects of MBRP augmented with transcutaneous vagus nerve stimulation (tVNS) or closed-loop amplitude-modulated transcranial alternating current stimulation (CLAM-tACS) on cognitive control, cue reactivity and interoceptive processing in AUD patients. Participants will undergo six weekly group MBRP sessions and daily individual mindfulness practices. Assessments will include an inhibition task, cue-induced craving task, and heartbeat discrimination task, alongside heart rate variability and 32-channel EEG recordings. Participants will be assessed pre and post treatment, with a three-month follow-up to evaluate long-term effects on abstinence and alcohol consumption. Discussion This study will not only elucidate the causal link between FMΘ and efficacy of MBRP, but contribute to a better understanding of how combined psychological and neuromodulation interventions can improve treatment outcomes for AUD, potentially leading to more effective therapeutic strategies. This study also seeks to explore individual differences in response to treatment, which could inform future approaches to AUD management. Trial registration This study received approval by the Charité—Universitätsmedizin Berlin Institutional Review Board (EA1/030/23, 10.11.2023). It was registered on ClinicalTrials.gov (NCT06308484).