Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Testing for Indeterminate Thyroid Nodules: Association of Negative Predictive Value With Nodule Size

Background Molecular testing helps stratify risk of malignancy in indeterminate thyroid nodules, but it may be limited in its ability to rule out malignancy in large nodules. Methods We compared small thyroid nodules (<4 cm) to large thyroid nodules (4 cm or greater) in a retrospective, single center, cohort study of indeterminate thyroid nodules analyzed with ThyroSeq from 10/2015 through 4/2020. Our primary outcome was negative predictive value. Results A total of 204 thyroid nodules were analyzed with ThyroSeq and 62 underwent resection allowing comparison to final pathology for 48 small nodules and 14 large nodules. A greater proportion of large nodules were observed in men (50.0% vs 18.8% in small nodules, P = .02), but median age was similar between the groups (49.0 vs 52.5 years, P = .95). False negative results comprised a higher proportion of tests for large nodules (14.3%) than small nodules (0%, P = .01). The negative predictive value of ThyroSeq in small nodules was 1 indicating a negative test reliably predicted a benign nodule, compared to . 5 in large nodules indicating a negative test in this cohort was reliable in predicting benignity. Applying the same negative predictive value to the cohort of large nodules that did not undergo resection after negative molecular testing (n = 16), it is possible that 8 large thyroid malignancies were missed at our institution during the study period. Conclusions Large thyroid nodules are associated with a higher rate of false negative results and a lower negative predictive value during molecular analysis of indeterminate thyroid nodules. Graphical Abstract
Association of ambient temperature and acute heart failure with preserved and reduced ejection fraction

Evidence on the association between ambient temperature and the onset of acute heart failure (AHF) is scarce and mixed. We sought to investigate the incidence of AHF admissions based on ambient temperature change, with particular interest in detecting the difference between AHF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF).
Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction

Physiologically‐based pharmacokinetic (PBPK) models have an important role in drug discovery/development and decision making in regulatory submissions. This is facilitated by predefined PBPK platforms with user‐friendly graphical interface, such as Simcyp and PK‐Sim. However, evaluations of platform differences and the potential implications for disposition‐related applications are still lacking. The aim of this study was to assess how PBPK model development, input parameters, and model output are affected by the selection of PBPK platform. This is exemplified via the establishment of simvastatin PBPK models (workflow, final models, and output) in PK‐Sim and Simcyp as representatives of established whole‐body PBPK platforms. The major finding was that the choice of PBPK platform influenced the model development strategy and the final model input parameters, however, the predictive performance of the simvastatin models was still comparable between the platforms. The main differences between the structure and implementation of Simcyp and PK‐Sim were found in the absorption and distribution models. Both platforms predicted equally well the observed simvastatin (lactone and acid) pharmacokinetics (20–80 mg), BCRP and OATP1B1 drug–gene interactions (DGIs), and drug–drug interactions (DDIs) when co‐administered with CYP3A4 and OATP1B1 inhibitors/inducers. This study illustrates that in‐depth knowledge of established PBPK platforms is needed to enable an assessment of the consequences of PBPK platform selection. Specifically, this work provides insights on software differences and potential implications when bridging PBPK knowledge between Simcyp and PK‐Sim users. Finally, it provides a simvastatin model implemented in both platforms for risk assessment of metabolism‐ and transporter‐mediated DGIs and DDIs.
Trauma exposure and eating disorders: Results from a United States nationally representative sample

Abstract Objective Sexual assault, child abuse, and combat have been linked to eating disorders (EDs). However, noninterpersonal trauma is relatively understudied, and therefore it is unknown whether noninterpersonal trauma is associated with EDs. Furthermore, most previous studies do not account for multiple trauma exposures, or the relative association of traumatic events with EDs in the same statistical model. Method Multinomial regression was used to examine the association of lifetime ED diagnosis (anorexia nervosa [AN], bulimia nervosa [BN], binge eating disorder [BED]) with trauma type (sexual interpersonal, other interpersonal, war/combat, and noninterpersonal) in a nationally representative dataset of US adults in bivariate and multivariable (i.e., with all trauma types) models. Results Sexual interpersonal trauma was significantly positively associated with AN and BED in bivariate and multivariable models. In the multivariable model, only BED was found to be equally associated with sexual interpersonal, other interpersonal, and noninterpersonal trauma. Discussion These results indicate a strong positive association between sexual trauma and EDs, even when controlling for experiences of other trauma events. Future research should examine longitudinal mediators between trauma and EDs, especially sexual trauma, to identify what factors may explain this relationship. Public significance statement Individuals with eating disorders often experience traumatic events but it is unclear whether specific trauma types are more or less common in this population. This study found that only events such as rape and sexual assault are associated with anorexia nervosa, but that most trauma types are associated with binge eating disorder. Therefore, the relationship between trauma and binge eating disorder may function differently than other eating disorders.
DMSO_A_313006 2851..2862

*These authors contributed equally to this work Background: The association between high-density lipoprotein cholesterol (HDL-C) and the risk of death among people with diabetes remains to be verified. Methods: This was a nationwide, population-based cohort study in United States. A total of 6549 diabetes patients were included from the National Health and Nutrition Examination Surveys (NHANES). HDL-C concentration was divided into quintiles, and the lowest risk group (Q4: 1.32 to 1.53 mmol/L) was used as reference. Multivariate Cox proportional hazards models and restrictive cubic curves were performed to estimate hazard ratios (HRs) with 95% confidence interval (CI) for all-cause and cause-specific mortality. Results: During a median follow-up of 82.36 ± 50.11 months, 1546 (23.61%) cases of allcause, 389 (5.94%) cardiovascular and 262 (4.00%) cancer mortality have occurred, respectively. After adjusting for potential covariates, a U-shaped association was found between HDL-C and all-cause mortality (minimum mortality risk at 1.37 mmol/L); the risk for allcause mortality was significantly higher in the groups with HDL-C concentration <0.96 mmol/L (HR: 1.30; 95% CI: 1.09, 1.56; P=0.0046) and with HDL-C concentration ≥1.55 mmol/L (HR: 1.20; 95% CI: 1.00, 1.44; P=0.0481) than participants with HDL-C concentrations ranging from 1.32 to 1.53mmol/L. Nonlinear associations of HDL-C levels with both cardiovascular and cancer mortality were also observed. Conclusion: A non-linear association was observed association of HDL-C with all-cause, cardiovascular and cancer mortality among diabetic patients.
Enterochromaffin Cells–Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction

Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells produce up to 95% of total body serotonin and coordinate luminal and basolateral communication in the gastrointestinal (GI) tract. EC cells affect a broad range of gut physiological processes, such as motility, absorption, secretion, chemo/mechanosensation, and pathologies, including visceral hypersensitivity, immune dysfunction, and impaired gastrointestinal barrier function. We aim to review EC cell and serotonin-mediated physiology and pathophysiology with particular emphasis on DGBIs. We explored the knowledge gap and attempted to suggest new perspectives of physiological and pathophysiological insights of DGBIs, such as (1) functional heterogeneity of regionally distributed EC cells throughout the entire GI tract; (2) potential pathophysiological mechanisms mediated by EC cell defect in DGBIs; (3) cellular and molecular mechanisms characterizing EC cells and gut microbiota bidirectional communication; (4) differential modulation of EC cells through GI segment-specific gut microbiota; (5) uncover whether crosstalk between EC cells and (i) luminal contents; (ii) enteric nervous system; and (iii) central nervous system are core mechanisms modulating gut-brain homeostasis; and (6) explore the therapeutic modalities for physiological and pathophysiological mechanisms mediated through EC cells. Insights discussed in this review will fuel the conception and realization of pathophysiological mechanisms and therapeutic clues to improve the management and clinical care of DGBIs.
Molecular and cellular biology of PCSK9: impact on glucose homeostasis

Abstract Proprotein convertase substilisin/kexin 9 (PCSK9) inhibitors (PCSK9i) revolutionised the lipid-lowering therapy. However, a risk of type 2 diabetes mellitus (T2DM) is evoked under PCSK9i therapy. In this review, we summarise the current knowledge on the link of PCSK9 with T2DM. A significant correlation was found between PCSK9 and insulin, homeostasis model assessment (HOMA) of insulin resistance and glycated haemoglobin. PCSK9 is also involved in inflammation. PCSK9 loss-of-function variants increased T2DM risk by altering insulin secretion. Local pancreatic low PCSK9 regulates β-cell LDLR expression which in turn promotes intracellular cholesterol accumulation and hampers insulin secretion. Nevertheless, the association of PCSK9 loss-of-function variants and T2DM is inconsistent. InsLeu and R46L polymorphisms were associated with T2DM, low HOMA for β-cell function and impaired fasting glucose, while the C679X polymorphism was associated with low fasting glucose in Black South African people. Hence, we assume that the impact of these variants on glucose homeostasis may vary depending on the genetic background of the studied populations and the type of effect caused by those genetic variants on the PCSK9 protein. Accordingly, these factors should be considered when choosing a genetic variant of PCSK9 to assess the impact of long-term use of PCSK9i on glucose homeostasis.
RING finger protein 128 (RNF128) regulates malignant biological behaviors of colorectal cancer cells via PI3K/AKT signaling pathway

This study was designed and conducted to clarify the impact of RNF128 expression on malignant biological behaviors of colorectal cancer (CRC) cells and the underlying mechanism. The expression of RNF128 in CRC tissues was analyzed using mRNA sequencing data of TCGA database and was validated by Western blot assay. The experimental studies on biological functions of RNF128 in vitro were conducted to assess its impact on the proliferation, apoptosis, and metastasis of CRC cells. Furthermore, tumor xenograft models in nude mice were established to investigate the relationship between RNF128 expression and tumor growth in vivo. The expression levels of both RNF128 mRNA and protein were significantly increased in CRC tissues (p < .001). The knockdown of RNF128 markedly suppressed the malignant phenotype of HCT116 and SW480 cells in vitro, including cell growth, antiapoptosis, migration, and invasion (p < .001). On the other hand, knockdown of RNF128 exerted a remarkable effect on the growth inhibition of tumor xenografts in vivo (p < .001). Further investigation revealed that RNF128 knockdown lead to a significant decrease in the expression of p‐AKT and p‐PI3K protein. More importantly, the proliferative, antiapoptotic, metastatic abilities of RNF128‐knockdown cells were markedly increased by 740 Y‐P treatment (p < .001). These findings further suggested that PI3K/AKT signaling pathway played a key role in RNF128‐mediated aggressive phenotype of CRC cells. RNF128 functions as a tumor promoter in the pathogenesis of CRC via regulating PI3K/AKT pathway, and it could be a valuable target for CRC treatment.
Circ_UBE2D2 Attenuates the Progression of Septic Acute Kidney Injury in Rats by Targeting miR-370-3p/NR4A3 Axis

As circ_UBE2D2 has been confirmed to have targeted binding sites with multiple miRNAs involved in septic acute kidney injury (SAKI), efforts in this study are directed to unveiling the specific role and relevant mechanism of circ_UBE2D2 in SAKI. HK-2 cells were treated with lipopolysaccharide (LPS) to construct SAKI model in vitro. After sh-circ_UBE2D2 was transfected into cells, the transfection efficiency was detected by qRT-PCR, cell viability and apoptosis were determined by MTT assay and flow cytometry, and expressions of Bcl-2, Bax and Cleaved-caspase 3 were quantified by western blot. Target genes associated with circ_UBE2D2 were predicted using bioinformatics analysis. After the establishment of SAKI rat model, HE staining and TUNEL staining were exploited to observe the effect of circ_UBE2D2 on tissue damage and cell apoptosis. The expression of circ_UBE2D2 was overtly elevated in LPS-induced HK-2 cells. Sh-circ_UBE2D2 can offset the inhibition of cell viability and the promotion of cell apoptosis induced by LPS. Circ_UBE2D2 and miR-370-3p as well as miR-370-3p and NR4A3 have targeted binding sites. MiR-370-3p inhibitor reversed the promoting effect of circ_UB2D2 silencing on viability of LPS-treated cells, but shNR4A3 neutralized the above inhibitory effect of miR-370-3p inhibitor. MiR-370-3p inhibitor weakened the down-regulation of NR4A3, Bax and Cleaved caspase-3 and the up-regulation of Bcl-2 induced by circ_UB2D2 silencing, but these trends were reversed by shNR4A3. In addition, sh-circ_UBE2D2 could alleviate the damage of rat kidney tissue. Circ_UBE2D2 mitigates the progression of SAKI in rats by targeting miR-370-3p/NR4A3 axis.
Poly-ε-caprolactone/poly(rotaxane) seeded with human dental pulp stem cells or osteoblasts promotes angiogenesis: a chorioallantoic membrane assay

Abstract Biomaterials used for tissue regeneration should ideally provide a favorable environment for cell proliferation and differentiation. Angiogenesis is crucial for supplying oxygen and nutrients necessary for cellular survival at implantation sites. The aim of this study was to evaluate the overall angiogenesis response of a poly ε-caprolactone/poly (rotaxane) blend (poly-blend) carried by human dental pulp stem cells (hDPSCs) or osteoblasts (OB) seeded in the chorioallantoic membranes (CAM) of fertilized chicken eggs on embryonic day 7. They were classified into the following intervention groups: (a) poly(polymeric blend disks free of cells); (b) hDPSC seeded onto CAM; (c) poly/hDPSC (where hDPSCs were seeded onto poly-blend); (d) poly/OB (where osteoblasts were seeded onto poly); (e) OB (where hDPSCs differentiated into osteoblasts were seeded onto CAM); and (f) a negative control when a sterilized silicone ring free of cells or polymer was inserted into CAM. On embryonic day 14, the quantitative and qualitative characteristics of the blood vessels in the CAMs were analyzed macroscopically and microscopically. Macroscopic examination showed that the Poly/hDPSC samples exhibited an increased medium vessel density. Additionally, microscopic observations showed that the Poly/hDPSC group and poly alone resulted in a large lumen area of vascularization. Thus, poly ε-caprolactone/poly (rotaxane) did not impair angiogenesis. Furthermore, poly-blend carried by stem cells of dental pulp origin shows a better vasculogenic potential, which is essential for regenerative therapies.
Melflufen for the treatment of multiple myeloma

ABSTRACT Introduction Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM). Areas covered This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed. Expert opinion Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study – currently under discussion with regulatory agencies in the United States and Europe – are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide–drug conjugate platform in relapsed/refractory MM.
REACT Aspiration Catheters: Clinical Experience and Technical Considerations

Aspiration catheters are widely used in mechanical thrombectomy procedures to treat acute ischemic stroke due to large vessel occlusion. The key performance requirements for aspiration catheters are ease of navigation and effective aspiration. In this work, we review the clinical experience and in vitro studies of REACT aspiration catheters (Medtronic, Minneapolis, MN, USA). In vitro experiments showed that REACT catheters exhibit solid performance in navigation and aspiration. Previous studies reported that the recanalization capacity of the aspiration catheters can be influenced by the devices’ inner diameter and tip distensibility, the catheter-to-vessel diameter ratio, the negative pressure delivered by the vacuum generator, the cyclical aspiration mode, the proximal flow arrest, and the angle of interaction between catheter and clot. REACT catheters can be navigated through the vasculature without any support from a microcatheter/ microwire in favorable anatomical configurations. In challenging situations, mostly encountered when crossing the ophthalmic segment of the internal carotid artery, the use of the stentriever anchoring technique or delivery assist catheter can facilitate the navigation. Three clinical studies reporting on 299 patients who underwent mechanical thrombectomy with REACT catheters were included in this review. Successful recanalization (modified treatment in cerebral ischemia score 2b–3) was achieved in 89–96% of cases, no procedural complications related to REACT catheters were reported, and functional independence (modified Rankin Scale 0–2) at 90-days was 24–36%. In vitro experimental evaluations and clinical studies support the safety and effectiveness of the REACT catheters.
Heart Failure And Type 2 Diabetes Mellitus: Neurohumoral, Histological And Molecular Interconnections

Heart failure (HF) is a global healthcare burden and a leading cause of morbidity and mortality worldwide. Type 2 diabetes mellitus (T2DM) appears to be one of the major risk factors that significantly worsen HF prognosis and increase the risk of fatal cardiovascular outcomes. Despite a great knowledge of pathophysiological mechanisms involved in HF development and progression, hospitalization rates in patients with HF and concomitant T2DM remain elevated. In this review, we discuss the complex interplay between systemic neurohumoral regulation and local cardiac mechanisms participating in myocardial remodeling and HF development in T2DM with special attention to cardiomyocyte energy metabolism, mitochondrial function and calcium metabolism, cardiomyocyte hypertrophy and death, extracellular matrix remodeling.
Impact of the Affordable Care Act on Glaucoma Severity at First Presentation

Abstract Purpose: To test whether the increase in insurance coverage in Massachusetts due to the Affordable Care Act (ACA) is associated with a decrease in glaucoma severity in patients presenting for the first time at a tertiary health system. Methods: Clinical and billing data of first-time glaucoma patients from a tertiary health system in Massachusetts from 2006 to 2021 was used. Pre-ACA is defined as before 2014 and post-ACA is defined as after 2014. Visual field mean deviation was used to define glaucoma severity: greater than -6 dB, less than -6 dB and greater than -12 dB, and less than -12 dB was classified as “mild,” “moderate,” and “severe” respectively. Ordinal logistic regression models adjusted for age, race, gender, and insurance type were used to determine the odds of presenting with more severe glaucoma. Results: 2,394 pre-ACA and 3,651 post-ACA first-time glaucoma patients were identified. There was no significant difference in the likelihood of more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.96; 95% CI 0.86-1.08; p=0.49) among the entire population. In stratified analyses, patients who utilized Medicaid for insurance had 52% decreased odds for presenting with more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.48; 95% CI 0.33-0.69; p<0.001). This remained significant after adjustment for age, race, and gender (adjusted OR=0.44; 95% CI 0.29-0.65; p<0.001). Conclusion: At a Massachusetts-based tertiary healthcare center, individuals on Medicaid were more likely to have more severe glaucoma at first presentation before the implementation of the ACA, compared to after.
Bride price, dowry, and young men with time to kill: A commentary on men’s marriage postponement in India

Rising numbers of young unmarried men in India reflect a marriage squeeze that goes beyond the shortage of brides created by sex-selective abortion. We describe a decline in men’s marriageability caused by their falling economic prospects at the same time as families of brides are increasingly seeking grooms with stable employment. We group young men into those without jobs or much education, those with education but no work, and the privileged few with education as well as employment. This classification resolves some of the seeming contradictions in the qualitative literature on marriage in India. Some of this literature talks about the rising prevalence of bride price and some about the persistence of dowry, while some papers reflect in general on the costs of being young, male, and aimless. Our commentary includes a review of the growing literature on the physiological and (perhaps) consequently behavioural and health outcomes of men’s anomie.