Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical outcomes of transcatheter aortic valve implantation in patients younger than 70 years rejected for surgery: the AMTRAC registry.

BACKGROUND The mean age of transcatheter aortic valve implantation (TAVI) patients is steadily decreasing. AIMS The aim of the study was to describe the characteristics, the indications for and the outcomes of TAVI in patients <70 years old. METHODS All patients undergoing TAVI (n=8,626) from the 18 participating centres between January 2007 and June 2020 were stratified by age ( 70). For patients <70, the indications for TAVI were extracted from Heart Team discussions and the baseline characteristics and mortality were compared between the two groups. RESULTS Overall, 640 (7.4%) patients were <70 (9.1% during 2018-2020, p<0.001); the mean age was 65.0±2.3 years. The younger patients were more often male, with bicuspid valves or needing valve-in-valve procedures. They had a higher prevalence of lung disease and diabetes. In 80.7% of cases, the Heart Team estimated an increased surgical risk and TAVI was selected, reflected by an STS score >4% in 20.4%. Five-year mortality was similar (29.4 vs 29.8%, HR 0.95, p=0.432) in the <70 and >70 groups. In the <70 group, mortality was higher for those referred for TAVI due to an increased surgical risk compared to those referred for other reasons (31.6 vs 24.5%, HR 1.23, p=0.021). Mortality was similar regardless of the STS stratum in patients judged by the Heart Team to be at increased surgical risk (32.6 vs 30.4%, HR 0.98, p=0.715). CONCLUSIONS Use of TAVI in patients <70 is becoming more frequent. The main reason for choosing TAVI is due to an increased surgical risk not adequately represented by the STS score. The outcomes for these patients are similar to those for older TAVI patients. Dedicated trials of TAVI/SAVR in younger patients are needed to guide decisions concerning expansion of TAVI indications. (NCT04031274).
Seek and Ye Shall Be Fine: Attitudes Toward Political-Perspective Seekers

Six preregistered studies (N = 2,421) examined how people respond to copartisan political-perspective seekers: political allies who attempt to hear from shared opponents and better understand their views. We found that North American adults and students generally like copartisan seekers (meta-analytic Cohen’s d = 0.83 across 4,231 participants, representing all available data points). People like copartisan perspective seekers because they seem tolerant, cooperative, and rational, but this liking is diminished because seekers seem to validate—and may even adopt—opponents’ illegitimate views. Participants liked copartisan seekers across a range of different motivations guiding these seekers’ actions but, consistent with our theorizing, their liking decreased (though rarely disappeared entirely) when seekers lacked partisan commitments or when they sought especially illegitimate beliefs. Despite evidence of rising political intolerance in recent decades, these findings suggest that people nonetheless celebrate political allies who tolerate and seriously consider their opponents’ views.
In Vitro and In Vivo Anti-Clostridioides difficile Effect of a Probiotic Bacillus amyloliquefaciens Strain

Clostridioides difficile infection (CDI) is a significant cause of hospital-acquired and antibiotic-mediated intestinal diseases and is a growing global public health concern. Overuse of antibiotics and their effect on normal intestinal flora has increased the incidence and severity of infections. Thus, the development of new, effective, and safe treatment options is a high priority. Here, we report a new probiotic strain, Bacillus amyloliquefaciens (BA PMC-80), and its in vitro/in vivo anti-C. difficile effect as a prospective novel candidate for replacing conventional antibiotics. BA PMC-80 showed a significant anti-C. difficile effect in coculture assay, and its cell-free supernatant (CFS) also exhibited a considerable anti-C. difficile effect with an 89.06 μg/ml 50% minimal inhibitory concentration (MIC) in broth microdilution assay. The CFS was stable and equally functional under different pHs, heat, and proteinase treatments. It also exhibited a high sensitivity against current antibiotics and no toxicity in subchronic toxicity testing in hamsters. Finally, BA PMC-80 showed a moderate effect in a hamster CDI model with reduced infection severity and delayed death. However, further studies are required to optimize the treatment condition of the hamster CDI model for better efficacy and identify the antimicrobial compound produced by BA PMC-80.
Fc gamma receptor IIIb binding of individual antibody proteoforms resolved by affinity chromatography–mass spectrometry

ABSTRACT The crystallizable fragment (Fc) of immunoglobulin G (IgG) activates key immunological responses by interacting with Fc gamma receptors (FcɣR). FcɣRIIIb contributes to neutrophil activation and is involved in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These processes present important mechanisms-of-actions of therapeutic antibodies. The very low affinity of IgG toward FcɣRIIIb (KD ~ 10 µM) is a technical challenge for interaction studies. Additionally, the interaction is strongly dependent on IgG glycosylation, a major contributor to proteoform heterogeneity. We developed an affinity chromatography–mass spectrometry (AC-MS) assay for analyzing IgG-FcɣRIIIb interactions in a proteoform-resolved manner. This proved to be well suited to study low-affinity interactions. The applicability and selectivity of the method were demonstrated on a panel of nine different IgG monoclonal antibodies (mAbs), including no-affinity, low-affinity and high-affinity Fc-engineered or glycoengineered mAbs. Thereby, we could reproduce reported affinity rankings of different IgG glycosylation features and IgG subclasses. Additional post-translational modifications (IgG1 Met252 oxidation, IgG3 hinge-region O-glycosylation) showed no effect on FcɣRIIIb binding. Interestingly, we observed indications of an effect of the variable domain sequence on the Fc-binding that deserves further attention. Our new AC-MS method is a powerful tool for expanding knowledge on structure–function relationships of the IgG-FcɣRIIIb interaction. Hence, this assay may substantially improve the efficiency of assessing critical quality attributes of therapeutic mAbs with respect to an important aspect of neutrophil activation.
ANT2 drives proinflammatory macrophage activation in obesity

Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid–induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).
Oral Health Status and Oral Health–Related Quality of Life of First Nations and Metis Children

Objectives: To assess the oral health status and oral health–related quality of life (OHRQoL) of young First Nations and Metis children. Methods: This cross-sectional study assessed the oral health status of Indigenous children <72 mo of age while their parents/caregivers completed a questionnaire, including the Early Childhood Oral Health Impact Scale (ECOHIS), to assess OHRQoL. Analysis included descriptive statistics, bivariate analyses, and multiple regression. A P value ≤0.05 was considered significant. Results: Overall, 146 children were recruited with a mean age of 40.1 ± 21.2 (SD) months, and 49% were male. Among First Nations children, 65.4% had early childhood caries (ECC) as compared with 45.2% among Metis children (P = 0.025). However, there was no statistically significant difference in the prevalence of severe ECC (S-ECC) between First Nations and Metis children (60.6% v. 42.9%, P = 0.051). The mean decayed, missing, and filled primary teeth (dmft) score was 4.9 ± 5.3 (range 0–20), and the mean decayed, missing, and filled surfaces (dmfs) score was 14.5 ± 20.4 (range 0–80). The total mean ECOHIS score was 4.4 ± 5.9 (range 0–25), while the mean Child Impact Section and Family Impact Section scores were 2.6 ± 4.0 (range 0–10) and 1.8 ± 2.8 (range 0–8), respectively. Multiple linear regression showed S-ECC was associated with total mean ECOHIS scores (P = 0.02). Higher total mean ECOHIS scores (which indicates poorer OHRQoL) were observed in children with ECC compared with caries-free children (5.8 v. 2.4, P = 0.0001). Conclusion: Oral health disparities such as ECC and reduced OHRQoL exist among many First Nations and Metis children in Manitoba. This is the first Canadian study exploring the OHRQoL of Indigenous children in addition to their oral health status. Knowledge Transfer Statement: This study is the first to report on the oral health–related quality of life and its relationship to early childhood caries (ECC) among young Canadian First Nations and Metis children. Metis children are just as likely to suffer from severe ECC than First Nations children. The findings of this study have informed community-based and community-developed oral health promotion and ECC prevention activities.
Combined supplementation of sodium humate and glutamine reduced diarrhea incidence of weaned calves by intestinal microbiota and metabolites changes.

This study was conducted to investigate the effects of combined supplementation of sodium humate (HNa) and glutamine (Gln) on growth performance, diarrhea incidence, serum parameters, intestinal microbiome, and metabolites of weaned calves. In Exp. 1, 40 calves were randomly assigned to 4 treatments (1) NC (negative control, basal diet), (2) 1% H+1% G (basal diet extra orally gavaged with 1 g of HNa and 1 g of Gln daily), (3) 3% H+1% G (basal diet extra orally gavaged with 3 g of HNa and 1 g of Gln daily), and (4) 5% H+1% G (basal diet extra orally gavaged with 5 g of HNa and 1 g of Gln daily). The HNa and Gln were together mixed with 100 mL of milk replacer (51-58 days of age) or water (59-72 days of age) and orally administrated to each calf from a bottle before morning feeding. In a 21-day trial, calves on the 5% HNa+1% Gln group had higher (P < 0.05) average daily gain (ADG) and lower (P < 0.05) diarrhea incidence than those in the control group. In Exp. 2, 20 calves were randomly assigned to 2 treatments fed with a basal diet and a basal diet supplemented with 100 mL of 5% HNa+1% Gln. In a 21-day trial, calves supplemented with HNa and Gln had higher (P < 0.05) ADG, IgG concentration and glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) activities in the serum, but lower (P < 0.05) diarrhea incidence, as well as serum diamine oxidase (DAO), D-isomer of lactic acid (D-lac), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) concentrations compared to control group. Results of intestinal microbiota indicated that supplementation with HNa and Gln significantly increased (P < 0.05) the abundance of intestinal beneficial microbiota. Moreover, supplementation with HNa and Gln altered 18 metabolites and enriched 6 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in weaned calves. In conclusion, combined supplementation with HNa and Gln could decrease diarrhea incidence of weaned calves via altering intestinal microbial ecology and metabolism profile.
Α case of seronegative autoimmune encephalitis associated with human herpesvirus‐7 (HHV‐7)

In the last 10 years, an increased number of patients presenting with acute encephalitis is being observed, a finding that is attributed to autoimmune mechanisms. Despite the fact that autoantibodies usually target the neuronal cell surface or synaptic proteins in the central nervous system (CNS), in many cases these remain undetectable, constituting a future diagnostic and therapeutic challenge. Human herpesvirus‐7 (HHV‐7) is proven to be a neurotropic virus, causing various neurological complications mostly in the adult population. We present the case of a 10‐year‐old girl, with confirmed active HHV‐7 infection of the CNS, who developed acute seronegative autoimmune encephalitis. To our best knowledge, there is no literature concerning pediatric cases of autoimmune encephalitis following HHV‐7 infection.
Graft Survivorship After Anterior Cruciate Ligament Reconstruction Based on Tibial Slope

Background: Increased tibial slope (TS) is believed to be a risk factor for anterior cruciate ligament (ACL) tears. Increased TS may also promote graft insufficiency after ACL reconstruction. Purpose: To delineate the relationship between TS and single as well as multiple graft insufficiencies after ACL reconstruction. Study Design: Cohort study; Level of evidence 3. Methods: We retrospectively identified 519 patients who had sustained ACL graft insufficiency after primary or revision ACL reconstruction (1 graft insufficiency, group A; 2 graft insufficiencies, group B; and ≥3 graft insufficiencies, group C). In addition, a subgroup analysis was conducted in 63 patients who received all surgical interventions by 2 specialized high-volume, single-center ACL surgeons. TS was measured by an observer with >10 years of training using lateral knee radiographs, and intrarater reliability was performed. Multiple logistic and univariate Cox regression was used to assess the contribution of covariates (TS, age, sex, and bilateral ACL injury) on repeated graft insufficiency and graft survival. Results: The study included 347 patients, 119 female and 228 male, who were 24 ± 9 years of age at their first surgery (group A, n = 260; group B, n = 62; group C, n = 25). Mean TS was 9.8°± 2.7° (range, 3°-18°). TS produced the highest adjusted odds ratio (1.73) of all covariates for repeated graft insufficiency. A significant correlation was found between TS and the number of graft insufficiencies (r = 0.48; P < .0001). TS was significantly lower in group A (9.0°± 2.3°) compared with group B (12.1°± 2.5°; P < .0001) and group C (12.0°± 2.6°; P < .0001). A significant correlation was seen between the TS and age at index ACL tear (r = −0.12; P = .02) as well as time to graft insufficiency (r = −0.12; P = .02). A TS ≥12° had an odds ratio of 11.6 for repeated ACL graft insufficiency. Conclusion: The current results indicate that patients with a markedly increased TS were at risk of early and repeated graft insufficiency after ACL reconstruction. Because the TS is rarely accounted for in primary and revision ACLR, isolated soft tissue procedures only incompletely address recurrent graft insufficiency in this subset of patients.
Identification of α-Glucosidase Inhibitors from Leaf Extract of Pepper (Capsicum spp.) through Metabolomic Analysis

Metabolomics and in vitro α-glucosidase inhibitory (AGI) activities of pepper leaves were used to identify bioactive compounds and select genotypes for the management of type 2 diabetes mellitus (T2DM). Targeted metabolite analysis using UPLC-DAD-QToF-MS was employed and identified compounds that belong to flavone and hydroxycinnamic acid derivatives from extracts of pepper leaves. A total of 21 metabolites were detected from 155 samples and identified based on MS fragmentations, retention time, UV absorbance, and previous reports. Apigenin-O-(malonyl) hexoside, luteolin-O-(malonyl) hexoside, and chrysoeriol-O-(malonyl) hexoside were identified for the first time from pepper leaves. Pepper genotypes showed a huge variation in their inhibitory activity against α-glucosidase enzyme(AGE) ranging from 17% to 79%. Genotype GP38 with inhibitory activity of 79% was found to be more potent than the positive control acarbose (70.8%.). Orthogonal partial least square (OPLS) analyses were conducted for the prediction of the AGI activities of pepper leaves based on their metabolite composition. Compounds that contributed the most to the bioactivity prediction model (VIP >1.5), showed a strong inhibitory potency. Caffeoyl-putrescine was found to show a stronger inhibitory potency (IC50 = 145 µM) compared to acarbose (IC50 = 197 µM). The chemometric procedure combined with high-throughput AGI screening was effective in selecting polyphenols of pepper leaf for T2DM management.
The Role of a Navigational Radiofrequency Ablation Device and Concurrent Vertebral Augmentation for Treatment of Difficult-to-Reach Spinal Metastases

Aims: The purpose of this study was to assess the effectiveness of a navigational radiofrequency ablation device with concurrent vertebral augmentation in the treatment of posterior vertebral body metastatic lesions, which are technically difficult to access. Primary outcomes of the study were evaluation of pain palliation and radiologic assessment of local tumor control. Materials and Methods: Thirty-five patients with 41 vertebral spinal metastases involving the posterior vertebral body underwent computed tomography-guided percutaneous targeted radiofrequency ablation, with a navigational radiofrequency ablation device, associated with vertebral augmentation. Twenty-one patients (60%) had 1 or 2 metastatic lesions (Group A) and fourteen (40%) patients had multiple (>2) vertebral lesions (Group B). Changes in pain severity were evaluated by visual analog scale (VAS). Metastatic lesions were evaluated in terms of radiological local control. Results: The procedure was technically successful in all the treated vertebrae. Among the symptomatic patients, the mean VAS score dropped from 5.7 (95% CI 4.9–6.5) before tRFA and to 0.9 (95% CI 0.4–1.3) after tRFA (p < 0.001). The mean decrease in VAS score between baseline and one week follow up was 4.8 (95% CI 4.2–5.4). VAS decrease over time between one week and one year following radiofrequency ablation was similar, suggesting that pain relief was immediate and durable. Neither patients with 1–2 vertebral metastases, nor those with multiple lesions, showed radiological signs of local progression or recurrence of the tumor in the index vertebrae during a median follow up of 19 months (4–46 months) and 10 months (4–37 months), respectively. Conclusion: Treatment of spinal metastases with a navigational radiofrequency ablation device and vertebral augmentation can be used to obtain local tumor control with immediate and durable pain relief, providing effective treatment in the multimodality management of difficult-to-reach spinal metastases.
Frailty and the Risk of Acute Kidney Injury Among Patients With Cirrhosis

Acute kidney injury (AKI) and frailty are major drivers of outcomes among patients with cirrhosis. What is unknown is the impact of physical frailty on the development of AKI. We included adults with cirrhosis without hepatocellular carcinoma listed for liver transplantation at nine US centers (n = 1,033). Frailty was assessed using the Liver Frailty Index (LFI); “frail” was defined by LFI ≥ 4.2. Chronic kidney disease as a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2. Our primary outcome, AKI, was defined as an increase in serum creatinine ≥0.3 mg/dL or a serum creatinine ≥1.5‐fold increase. Wait‐list mortality was defined as either a death on the wait list or removal for being too sick. We performed Cox regression analyses to estimate the hazard ratios (HRs) for AKI and wait‐list mortality. Of 1,033 participants, 41% were frail and 23% had CKD. Twenty‐one percent had an episode of AKI during follow‐up. Frail versus nonfrail patients were more likely to develop AKI (25% vs. 19%) and wait‐list mortality (21% vs. 13%) (P < 0.01 for each). In multivariable Cox regression, each of the following groups was associated with a higher risk of AKI as compared with not frail/no CKD: frail/no CKD (adjusted HR [aHR] = 1.87, 95% confidence interval [CI] = 1.29‐2.72); not frail/CKD (aHR = 4.30, CI = 2.88‐6.42); and frail/CKD (aHR = 4.85, CI = 3.33‐7.07). We use a readily available metric, LFI, to identify those patients with cirrhosis most at risk for AKI. We highlight that serum creatinine and creatinine‐based estimations of glomerular filtration rate may not fully capture a patient’s vulnerability to AKI among the frail phenotype. Conclusion: Our work lays the foundation for implementing physical frailty in clinical practice to identify AKI earlier, implement reno‐protective strategies, and expedite liver transplantation.
The beta2‐adrenergic receptor – a re‐emerging target to combat obesity and induce leanness?

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2‐adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta2‐adrenergic receptor in obesity. Specific human beta2‐adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundance of beta2‐adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2‐agonists induce a so‐called ‘repartitioning effect’ characterized by muscle accretion and reduced fat deposition. In humans, beta2‐agonists dose‐dependently increase resting metabolic rate by 10–50%. And like that observed in other mammals, only a few weeks of treatment with beta2‐agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2‐agonists also exert beneficial effects on body composition when used concomitantly with training and act additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2‐adrenergic receptor seems like an attractive target in the development of anti‐obesity drugs. However, future studies need to verify the long‐term efficacy and safety of beta2‐agonists in individuals with obesity, particularly in those with comorbidities.
Study on the Mechanism of the Blood-Glucose-Lowering Effect of Collagen Peptides from Sturgeon By-Products

In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.