Miracle-dz/UniFAR-FTUs huggingface dataset:
Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial.

OBJECTIVE Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.
Unpacking Violent Behavior in Young Adulthood: The Relative Importance of Hazardous Alcohol Use

Young adulthood is an important developmental period for investigating the nature of violent behavior. This study examines the unique contribution of alcohol use to violence perpetration among young adults in the Australian community, after accounting for the influence of sociodemographic, early life, trait, and well-being influences. Cross-sectional, self-report data was collected from 507 young adults aged 18-20 years in the Australian general community via an online survey. Sequential logistic regressions examined the relative and independent contribution of adverse childhood experiences (ACEs), impulsivity, psychological distress, and hazardous alcohol use to past-year violent behavior. Results show one in eight young adults aged 18-20 (13%) reported at least one act of violent behavior in the past year, primarily assault perpetrated against another person. Sequential logistic regression identified that after controlling for other risk factors, the number of ACEs reported and hazardous alcohol use were independently and positively associated with increased odds of reporting violent behavior in young adulthood. These findings demonstrate that ACEs and hazardous alcohol use are important, independent correlates of violent behavior in young adults. While preventing early adversity is key for reducing violence in the community, this evidence suggests that it is also important to target proximal causes such as hazardous alcohol use. Increasing early and widespread access to evidence-based, trauma-informed violence-prevention programs targeting risk factors across multiple settings is critical for reducing harm and supporting young people into healthy adulthood.
Texture, hedonic test and fatty acid profile of goat cheese with L plantarum TW14 and L. rhamnosus TW2 isolates stored at different temperature conditions

The purpose of this research was to investigate texture, hedonic test and fatty acids profile of goat cheese stored at cold and frozen temperatures for 60 days. Cheese was manufactured from goat milk with addition of probiotics bacteria L.plantarum TW14 and L.rhamnosusTW2 with a ratio of (1:1/v/v). Treatments were arranged in a factorial design, employing two factors, i.e. temperature (cold; frozen) and storage time (0; 15,30,45 and 60 days). Each treatment was repeated three times. Results showed that goat cheese stored at cold temperature has an average hardness-texture of 374.46 ±77.69 gf while that of the cheese stored at frozen temperature has 221.66 ±38.46 gf, which were significantly different (P<0.05). In term of flavor, texture and overall acceptability, there were no significant effects (P>0.05) of storage temperatures and storage time. However, the taste of cheese stored under cold and frozen temperatures was highly significant different (P<0.01). Fatty acids composition of cheese stored for 60 days in a cold storage showed that the highest fatty acid content was SFA which was 64.34% and USFA was 16.76%. During the 60-day storage, the SFA percentage of was relatively stable while the percentage of oleic acid USFA increased.
Characteristics of Cases with Poor Transcranial Motor-evoked Potentials Baseline Waveform Derivation in Spine Surgery

In a prospective multicenter study, 73 cases (2%) had poor baseline waveform derivation of transcranial motor-evoked potentials (Tc-MEPs) in 3625 patients who underwent spinal surgery at 16 spine centers. Poor baseline waveform derivation was significantly associated with thoracic lesions, motor deficit of manual muscle testing <3, high-risk surgery, and surgery for ossification of the posterior longitudinal ligament. Study Design. Prospective multicenter study. Objective. The purpose of the study is to examine cases with poor baseline waveform derivation for all muscles in multichannel monitoring of transcranial motor-evoked potentials (Tc-MEPs) in spine surgery. Summary of Background Data. Intraoperative neuromonitoring (IONM) is useful for identifying neurologic deterioration during spinal surgery. Tc-MEPs are widely used for IONM, but some cases have poor waveform derivation, even in multichannel Tc-MEP monitoring. Methods. The subjects were 3625 patients (mean age 60.1 years, range 4–95; 1886 females, 1739 males) who underwent Tc-MEP monitoring during spinal surgery at 16 spine centers between April 2017 and March 2020. Baseline Tc-MEPs were recorded from the deltoid, abductor pollicis brevis, adductor longus, quadriceps femoris, hamstrings, tibialis anterior, gastrocnemius, and abductor hallucis (AH) muscles after surgical exposure of the spine. Results. The 3625 cases included cervical, thoracic, and lumbar lesions (50%, 33% and 17%, respectively) and had preoperative motor status of no motor deficit, and motor deficit with manual muscle testing (MMT) ≥3 and MMT <3 (70%, 24% and 6%, respectively). High-risk surgery was performed in 1540 cases (43%). There were 73 cases with poor baseline waveform derivation (2%), and this was significantly associated with higher body weight, body mass index, thoracic lesions, motor deficit of MMT <3, high-risk surgery (42/1540 [2.7%] vs. 31/2085 [1.5%], P < 0.05), and surgery for ossification of the posterior longitudinal ligament (OPLL). Intraoperative waveform derivation occurred in 25 poor derivation cases (34%) and the AH had the highest rate. Conclusion. The rate of poor baseline waveform derivation in spine surgery was 2% in our series. This was significantly more likely in high-risk surgery for thoracic lesions and OPLL, and in cases with preoperative severe motor deficit. In such cases, it may be preferable to use multiple modalities for IONM to derive multichannel waveforms from distal limb muscles, including the AH. Level of Evidence: 3
A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART, SWOG S1609)

Purpose: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). Patients and Methods: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Overall, 17 evaluable patients enrolled. Median age was 60 years (26–85); median number of prior therapy lines was 2 (0–5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. Conclusions: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.
Self-supervised Human Detection and Segmentation via Background Inpainting

While supervised object detection and segmentation methods achieve impressive accuracy, they generalize poorly to images whose appearance significantly differs from the data they have been trained on. To address this when annotating data is prohibitively expensive, we introduce a self-supervised detection and segmentation approach that can work with single images captured by a potentially moving camera. At the heart of our approach lies the observation that object segmentation and background reconstruction are linked tasks, and that, for structured scenes, background regions can be re-synthesized from their surroundings, whereas regions depicting the moving object cannot. We encode this intuition into a self-supervised loss function that we exploit to train a proposal-based segmentation network. To account for the discrete nature of the proposals, we developed a Monte Carlo-based training strategy that allows the algorithm to explore the large space of object proposals. We apply our method to human detection and segmentation in images that visually depart from those of standard benchmarks and outperform existing self-supervised methods.
The use of noninvasive brain stimulation techniques to improve reading difficulties in dyslexia: A systematic review

Noninvasive brain stimulation (NIBS) allows to actively and noninvasively modulate brain function. Aside from inhibiting specific processes, NIBS may also enhance cognitive functions, which might be used for the prevention and intervention of learning disabilities such as dyslexia. However, despite the growing interest in modulating learning abilities, a comprehensive, up‐to‐date review synthesizing NIBS studies with dyslexics is missing. Here, we fill this gap and elucidate the potential of NIBS as treatment option in dyslexia. The findings of the 15 included studies suggest that repeated sessions of reading training combined with different NIBS protocols may induce long‐lasting improvements of reading performance in child and adult dyslexics, opening promising avenues for future research. In particular, the “classical” reading areas seem to be most successfully modulated through NIBS, and facilitatory protocols can improve various reading‐related subprocesses. Moreover, we emphasize the need to further explore the potential to modulate auditory cortex function as a preintervention and intervention approach for affected children, for example, to avoid the development of auditory and phonological difficulties at the core of dyslexia. Finally, we outline how future studies may increase our understanding of the neurobiological basis of NIBS‐induced improvements in dyslexia.
Proenkephalin and the risk of new‐onset heart failure: data from prevention of renal and vascular end‐stage disease

Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new‐onset HF in the general population remains to be established.
Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa

Factor XI (FXI) inhibition offers the promise of hemostasis‐sparing anticoagulation for the prevention and treatment of thromboembolic events. Abelacimab (MAA868) is a novel fully human monoclonal antibody that targets the catalytic domain and has dual activity against the inactive zymogen Factor XI and the activated FXI.
Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Description A lung cancer–specific form of CD8+ T cell dysfunction is established during T cell priming and contributes to ICB resistance. A unique T cell subset in lung cancer Although some non–small cell lung cancers (NSCLC) are sensitive to immune checkpoint blockade (ICB), many patients with NSCLC do not respond to ICB, which may relate to the lack of infiltration of CD8+ T cells. Here, Horton et al. used mouse models of flank and lung tumors to show that CD8+ T cells from lung tumors, not flank tumors, had a dysfunctional phenotype distinct from conventional T cell exhaustion that was established in the draining lymph node and correlated to ICB resistance. IL-2 and IL-12 treatment rescued this phenotype, leading to control of lung tumors. These data suggest that cytokine therapy might be able to rescue a specific subset of dysfunctional T cells found in lung tumors. In non–small cell lung cancer (NSCLC), response to immune checkpoint blockade (ICB) is associated with programmed cell death ligand 1 expression that is induced by interferon-γ–producing, tumor-infiltrating CD8+ T cells. However, not all tumors with a CD8+ T cell infiltrate respond to ICB, and little is known about the mechanisms governing ICB resistance in T cell–infiltrated NSCLC. We used an orthotopic NSCLC mouse model to study ICB-refractory CD8+ T cell responses. Single-cell RNA sequencing of the NSCLC mouse tumors revealed that lung cancer–specific tumor-infiltrating CD8+ T cells exhibited clonal expansion but lacked expression of genes associated with effector and exhausted T cell responses, indicating that they underwent a differentiation program distinct from conventional T cell exhaustion. This lung cancer–specific T cell dysfunction program was established early during priming in the mediastinal lymph node and was characterized by robust proliferation but a failed up-regulation of effector and exhausted T cell characteristics. Intriguingly, CD8+ T cells from patients with NSCLC expressed an analogous gene expression program, which appeared distinct from conventional T cell exhaustion. Administration of recombinant interleukin-2 (IL-2) and IL-12 was sufficient to restore effector T cell differentiation and induce control of KP lung tumors. These findings imply that a CD8+ T cell differentiation trajectory, activated during T cell priming in the mediastinal lymph node, limits the response of CD8+ T cells to ICB and thereby may contribute to failure of ICB in a subset T cell–infiltrated NSCLC.
Morphological landscapes from high content imaging reveal cytokine priming strategies that enhance mesenchymal stromal cell immunosuppression

Successful clinical translation of mesenchymal stromal cell (MSC) products has not been achieved in the United States and may be in large part due to MSC functional heterogeneity. Efforts have been made to identify “priming” conditions that produce MSCs with consistent immunomodulatory function; however, challenges remain with predicting and understanding how priming impacts MSC behavior. The purpose of this study was to develop a high throughput, image‐based approach to assess MSC morphology in response to combinatorial priming treatments and establish morphological profiling as an effective approach to screen the effect of manufacturing changes (i.e., priming) on MSC immunomodulation. We characterized the morphological response of multiple MSC lines/passages to an array of Interferon‐gamma (IFN‐γ) and tumor necrosis factor‐⍺ (TNF‐⍺) priming conditions, as well as the effects of priming on MSC modulation of activated T cells and MSC secretome. Although considerable functional heterogeneity, in terms of T‐cell suppression, was observed between different MSC lines and at different passages, this heterogeneity was significantly reduced with combined IFN‐γ/TNF‐⍺ priming. The magnitude of this change correlated strongly with multiple morphological features and was also reflected by MSC secretion of immunomodulatory factors, for example, PGE2, ICAM‐1, and CXCL16. Overall, this study further demonstrates the ability of priming to enhance MSC function, as well as the ability of morphology to better understand MSC heterogeneity and predict changes in function due to manufacturing.
Social acceptability of standard and behavioral economic inspired policies designed to reduce and prevent obesity

Abstract The obesity epidemic is a significant public policy issue facing the international community, resulting in substantial costs to individuals and society. Various policies have been suggested to reduce and prevent obesity, including those informed by standard economics (a key feature of which is the assumption that individuals are rational) and behavioral economics (which identifies and harness deviations from rationality). It is not known which policy interventions taxpayers find acceptable and would prefer to fund via taxation. We provide evidence from a discrete choice experiment on an Australian sample of 996 individuals to investigate social acceptability of eight policies: mass media campaign; traffic light nutritional labeling; taxing sugar sweetened beverages; prepaid cards to purchase healthy food; financial incentives to exercise; improved built environment for physical activity; bans on advertising unhealthy food and drink to children; and improved nutritional quality of food sold in public institutions. Latent class analysis revealed three classes differing in preferences and key respondent characteristics including capacity to benefit. Social acceptability of the eight policies at realistic levels of tax increases was explored using post‐estimation analysis. Overall, 78% of the sample were predicted to choose a new policy, varying from 99% in those most likely to benefit from obesity interventions to 19% of those least likely to benefit. A policy informed by standard economics, traffic light labeling was the most popular policy, followed by policies involving regulation: bans on junk food advertising to children and improvement of food quality in public institutions. The least popular policies were behaviorally informed: prepaid cards for the purchase of only healthy foods, and financial incentives to exercise.
Probing peptide nanowire conductivity by THz nanoscopy

Significant efforts have recently been invested in assessing the physical and chemical properties of microbial nanowires for their promising role in developing alternative renewable sources of electricity, bioelectronic materials and implantable sensors. One of their outstanding properties, the ever-desirable conductivity has been the focus of numerous studies. However, the lack of a straightforward and reliable method for measuring it seems to be responsible for the broad variability of the reported data. Routinely employed methods tend to underestimate or overestimate conductivity by several orders of magnitude. In this work, synthetic peptide nanowires conductivity is interrogated employing a non-destructive measurement technique developed on a terahertz scanning near-field microscope to test if peptide aromaticity leads to higher electrical conductivity. Our novel peptide conductivity measurement technique, based on triple standards calibration method, shows that in the case of two biopolymer mimicking peptides, the sample incorporating aromatic residues (W6) is about six times more conductive than the negative control (L6). To the best of our knowledge, this is the first report of a quantitative nano-scale terahertz s-SNOM investigation of peptides. These results prove the suitability of the terahertz radiation-based non-destructive approach in tandem with the designer peptides choice as model test subjects. This approach requires only simple sample preparation, avoids many of the pitfalls of typical contact-based conductivity measurement techniques and could help understanding fundamental aspects of nature’s design of electron transfer in biopolymers.
Independent effects of amyloid and vascular markers on long‐term functional outcomes: An 8‐year longitudinal study of subcortical vascular cognitive impairment

Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long‐term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality.
SCMGR: Using Social Context and Multi-Granularity Relations for Unsupervised Social Summarization

Social summarization aims to produce a concise summary that describes the core content of a collection of posts on a specific topic. Existing methods tend to produce sparse or ambiguous representations of posts due to only using short and informal text content. Latest researches use social relations to improve diversity of summaries, yet they model social relations as a regularization item, which has poor flexibility and generalization. Those methods could not embody the deep semantic and social interactions among posts, making summaries still suffer from redundancy. We propose to use Social Context and Multi-Granularity Relations (SCMGR) to improve unsupervised social summarization. It learns more informative representations of posts considering both text semantics and social structure information without any annotated data. First, we design two sociologically motivated meta-paths to construct a social context graph among posts, and adopt a graph convolutional network to aggregate social context information from neighbors. Second, we design a multi-granularity relation decoder to capture the deeper semantic and social interactions from post-word and post-post aspects respectively, which can provide guidance for summary selection from semantic and social structure perspectives. Finally, a sparse reconstruction-based extractor is used to select posts that can best reconstruct original content and social network structure as summaries. Our approach improves the coverage and diversity of summaries. Experimental results on both English and Chinese corpora prove the effectiveness of our model.