Miracle-dz/UniFAR-FTUs huggingface dataset:
Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications

Background Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. Results Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. Conclusions There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.
Current Testing Guidelines: A Retrospective Analysis of a Community-Based Hereditary Cancer Program

It is estimated that 5% to 10% of all cancers are related to a hereditary cancer syndrome. However, specific cancers, such as pancreatic and ovarian cancers, are related to hereditary cancer syndromes 15% to 20% of the time. Genetic testing guidelines for hereditary cancer syndromes are frequently reviewed and updated by the National Comprehensive Cancer Network (NCCN). The purpose of this retrospective analysis is to identify carriers of pathogenic variants or hereditary cancer syndrome who do not meet NCCN criteria for testing and compare the results with previous studies. The data obtained can be used to provide recommendations to assess current guidelines for testing and evaluate the benefit of comprehensive panel testing vs. standard testing for specific hereditary cancer syndromes. This project is a retrospective review of clinical histories of patients who had multigene panel testing between September 2015 and February 2019 through a cancer outreach and risk assessment (CORA) program. Frequencies analyses were performed to analyze results. A total of 233 individuals were included in the analysis: 171 met BRCA1/2 testing criteria, 66 met Lynch syndrome criteria, and 4 met polyposis criteria. Of the individuals meeting established criteria for testing, 39 were identified with pathogenic variants. However, only 10 of these individuals were identified with a pathogenic variant associated with the criteria for which they met. Genetic testing that is limited to only those patients with genes associated with hereditary cancer syndromes may lead to exclusion of other potentially actionable genes, which may impair a patient's ability to receive additional screening or preventative measures.
Propensity to intentional and unintentional mind-wandering differs in arousal and executive vigilance tasks

We typically observe a decrement in vigilance with time-on-task, which favors the propensity for mind-wandering, i.e., the shifting of attention from the task at hand to task-unrelated thoughts. Here, we examined participants’ mind-wandering, either intentional or unintentional, while performing vigilance tasks that tap different components of vigilance. Intentional mind-wandering is expected mainly when the arousal component is involved, whereas unintentional mind-wandering is expected mainly in tasks involving the executive component. The Psychomotor Vigilance Task (PVT) assessed the arousal component, whereas the Sustained Attention to Response task (SART) assessed the executive component of vigilance. The two types of mind-wandering were probed throughout task execution. The results showed that the overall rate of mind-wandering was higher in the PVT than in the SART. Intentional mind-wandering was higher with the PVT than with the SART, whereas unintentional mind-wandering was higher with the SART than with the PVT. Regarding mind-wandering as a function of vigilance decrement with time-on-task, unintentional mind-wandering in the PVT increased between blocks 1 and 2 and then stabilized, whereas a progressive increase was observed in the SART. Regarding intentional mind-wandering, a progressive increase was only observed in the SART. The differential patterns of intentional and unintentional mind-wandering in both tasks suggest that, intentional mind wandering occurs mainly in arousal tasks in which propensity to mind-wander has little impact on task performance. However, unintentional mind-wandering occurs mainly in executive tasks as a result of a failure of cognitive control, which promotes attentional resources to be diverted toward mind-wandering. These results are discussed in the context of the resource-control model of mind-wandering.
Improvement of 2-phenylethanol production in Saccharomyces cerevisiae by evolutionary and rational metabolic engineering

2-Phenylethanol (2-PE) is a valuable aromatic compound with favorable flavors and good properties, resulting in its widespread application in the cosmetic, food and medical industries. In this study, a mutant strain, AD032, was first obtained by adaptive evolution under 2-PE stress. Then, a fusion protein from the Ehrlich pathway, composed of tyrB from Escherichia coli, kdcA from Lactococcus lactis and ADH2 from Saccharomyces cerevisiae, was constructed and expressed. As a result, 3.14 g/L 2-PE was achieved using L-phenylalanine as a precursor. To further increase 2-PE production, L-glutamate oxidase from Streptomyces overexpression was applied for the first time in our research to improve the supply of α-ketoglutarate in the transamination of 2-PE synthesis. Furthermore, we found that the disruption of the pyruvate decarboxylase encoding gene PDC5 caused an increase in 2-PE production, which has not yet been reported. Finally, assembly of the efficient metabolic modules and process optimization resulted in the strain RM27, which reached 4.02 g/L 2-PE production from 6.7 g/L L-phenylalanine without in situ product recovery. The strain RM27 produced 2-PE (0.8 mol/mol) with L-phenylalanine as a precursor, which was considerably high, and displayed manufacturing potential regarding food safety and process simplification aspects. This study suggests that innovative strategies regarding metabolic modularization provide improved prospects for 2-PE production in food exploitation.
Structure prediction of honey bee vitellogenin: a multi‐domain protein important for insect immunity

Vitellogenin (Vg) has been implicated as a central protein in the immunity of egg‐laying animals. Studies on a diverse set of species suggest that Vg supports health and longevity through binding to pathogens. Specific studies of honey bees (Apis mellifera) further indicate that the vitellogenin (vg) gene undergoes selection driven by local pathogen pressures. Determining the complete 3D structure of full‐length Vg (flVg) protein will provide insights regarding the structure–function relationships underlying allelic variation. Honey bee Vg has been described in terms of function, and two subdomains have been structurally described, while information about the other domains is lacking. Here, we present a structure prediction, restrained by experimental data, of flVg from honey bees. To achieve this, we performed homology modeling and used AlphaFold before using a negative‐stain electron microscopy map to restrict, orient, and validate our 3D model. Our approach identified a highly conserved Ca2+‐ion‐binding site in a von Willebrand factor domain that might be central to Vg function. Thereafter, we used rigid‐body fitting to predict the relative position of high‐resolution domains in a flVg model. This mapping represents the first experimentally validated full‐length protein model of a Vg protein and is thus relevant for understanding Vg in numerous species. Our results are also specifically relevant to honey bee health, which is a topic of global concern due to rapidly declining pollinator numbers.
Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis

Background and Objectives In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation. Methods To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85). Results Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS. Discussion Our data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.
The profile of real-time competition in spoken and written word recognition: More similar than different

Word recognition occurs across two sensory modalities: auditory (spoken words) and visual (written words). While each faces different challenges, they are often described in similar terms as a competition process by which multiple lexical candidates are activated and compete for recognition. While there is a general consensus regarding the types of words that compete during spoken word recognition, there is less consensus for written word recognition. The present study develops a novel version of the Visual World Paradigm (VWP) to examine written word recognition and uses this to assess the nature of the competitor set during word recognition in both modalities using the same experimental design. For both spoken and written words, we found evidence for activation of onset competitors (cohorts, e.g., cat, cap) and words that contain the same phonemes or letters in reverse order (anadromes, e.g., cat, tack). We found no evidence of activation for rhymes (e.g., cat, hat). The results across modalities were quite similar, with the exception that for spoken words, cohorts were more active than anadromes, whereas for written words activation was similar. These results suggest a common characterisation of lexical similarity across spoken and written words: temporal or spatial order is coarsely coded, and onsets may receive more weight in both systems. However, for spoken words, temporary ambiguity during the moment of processing gives cohorts an additional boost during real-time recognition.
Cardiometabolic, Lifestyle, and Nutritional Factors in Relation to Varicose Veins: A Mendelian Randomization Study

Background We conducted a 2‐sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single‐nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25‐hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome‐wide significance level were used as instrumental variables. Summary‐level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1‐SD increase in the exposure were 1.34 (95% CI, 1.25–1.43) for height, 1.39 (95% CI, 1.27–1.52) for body mass index, 1.12 (95% CI, 1.04–1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16–1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62–0.92) per 1‐SD increase in calcium levels and 0.97 (95% CI, 0.95–0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.
Genetic factors in precocious puberty

Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors. Most cases of precocious puberty (PP) are diagnosed as central PP (CPP), defined as premature activation of the HPG axis. The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. Other genes, such as gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3), have been implicated in the progression of ICPP, although their relationships require elucidation. Environmental and socioeconomic factors may also be correlated with ICPP. In the progression of CPP, epigenetic factors such as DNA methylation, histone posttranslational modifications, and noncoding ribonucleic acids may mediate the relationship between genetic and environmental factors. CPP is correlated with short- and long-term adverse health outcomes, which forms the rationale for research focusing on understanding its genetic and nongenetic factors.
The effect of handrail cross-sectional design and age on applied handrail forces during reach-to-grasp balance reactions

Handrails have been shown to reduce the likelihood of falls. Despite common use, little is known about how handrail shape and size affect the forces that people can apply after balance loss, and how these forces and the corresponding ability to recover balance depend on age. Following rapid platform translations, 16 older adults and 16 sex-matched younger adults recovered their balance using seven handrail cross-sections varying in shape and size. Younger adults were able to withstand higher perturbations, but did not apply higher forces, than older adults. However, younger adults achieved their peak resultant force more quickly, which may reflect slower rates of force generation with older adults. Considering handrail design, the 38mm round handrails allowed participants to successfully recover from the largest perturbations and enabled the highest force generation. Conversely, tapered handrails had the poorest performance, resulting in the lowest force generation and withstood perturbation magnitudes. Our findings suggest that the handrail cross-sectional design affects the magnitude of force generation and may impact the success of recovery. Our findings can inform handrail design recommendations that support effective handrail use in demanding, balance recovery scenarios.
PARP inhibitors: clinical relevance and the role of multidisciplinary cancer teams on drug safety

ABSTRACT Introduction Cancer is considered one of the most devastating causes of death for humanity. Innovative and targeted therapies have become urgent in the treatment of this large subset of diseases. Over the last decade, the development of PARP (poly (ADP-Ribose) polymerase) inhibitors has emerged as a new target in cancer therapy. Areas covered The authors conducted a review focusing on the clinic relevance and adverse effects of the four drugs already approved by drug regulatory agencies, namely: olaparib, rucaparib, niraparib and talazoparib. Despite the targeted action of this drug class, the adverse effects should be carefully monitored for the adequate safety of cancer patients taking them. The role of multidisciplinary cancer teams is crucial to help more and more patients to benefit from these revolutionary agents. Expert opinion PARP (poly (ADP-Ribose) polymerase) inhibitors are drugs with great potential in the treatment of several types of cancer. However, their toxicity profiles often lead to treatment interruption or early discontinuation. The daily monitoring of these cancer patients by multidisciplinary cancer teams is essential for the success of therapy and for the promotion of a better quality of life.
Antibody response elicited by a third boost dose of inactivated SARS-CoV-2 vaccine can neutralize SARS-CoV-2 variants of concern

Neutralizing antibodies waned significantly six months after two-dose procedure of inactivated SARS-CoV-2 vaccine. However, it is not clear whether a third booster dose could quickly activate the body's immune response against the emerging SARS-CoV-2 variants. This study demonstrated that after a third booster dose of inactivated vaccine, immune memory can be quickly awakened, and the antibody response recovered after seven days. Importantly, although the titers decreased, the neutralizing antibodies at 14 days after the third dose can still neutralize alpha, beta, and delta variants.
Analysis of water distribution in delipidated human hair by small‐angle neutron scattering (SANS)

It is known that damaged hair has a part of its internal structure damaged, and its water absorption and desorption behavior are different. In recent years, it has been reported that internal lipids play an important role in the adsorption and desorption of water to the hair. Therefore, we investigate whether the water distribution in hair and the amount of internal lipids are related.
Bile acid-independent protection against Clostridioides difficile infection

Clostridioides difficile infections occur upon ecological / metabolic disruptions to the normal colonic microbiota, commonly due to broad-spectrum antibiotic use. Metabolism of bile acids through a 7α-dehydroxylation pathway found in select members of the healthy microbiota is regarded to be the protective mechanism by which C. difficile is excluded. These 7α-dehydroxylated secondary bile acids are highly toxic to C. difficile vegetative growth, and antibiotic treatment abolishes the bacteria that perform this metabolism. However, the data that supports the hypothesis that secondary bile acids protect against C. difficile infection is supported only by in vitro data and correlative studies. Here we show that bacteria that 7α-dehydroxylate primary bile acids protect against C. difficile infection in a bile acid-independent manner. We monoassociated germ-free, wildtype or Cyp8b1-/- (cholic acid-deficient) mutant mice and infected them with C. difficile spores. We show that 7α-dehydroxylation (i.e., secondary bile acid generation) is dispensable for protection against C. difficile infection and provide evidence that Stickland metabolism by these organisms consumes nutrients essential for C. difficile growth. Our findings indicate secondary bile acid production by the microbiome is a useful biomarker for a C. difficile-resistant environment but the microbiome protects against C. difficile infection in bile acid-independent mechanisms.
Microcirculation of intramyocardial hemorrhage caused by reperfused myocardial infarctions with ultrasmall superparamagnetic iron oxide cardiac magnetic resonance imaging

Background The actual role of the coronary microcirculation, which is massively injured by myocardial infarction (MI), in intramyocardial hemorrhage (IMH) pathophysiology is still not fully understood. Purpose To determine the change and distribution of microcirculation of myocardial edema (ME), IMH, MI, and the remote area of early reperfusion using 7.0-T cardiovascular magnetic resonance (CMR) in a rat model of acute MI. Material and Methods Eight rats with 60-min myocardial ischemia followed by reperfusion were investigated. On days 2 and 7, after the acquisition of T2*-mapping and T2-mapping images, late gadolinium enhancement imaging was performed to evaluate the extent of myocardial ischemia after an injection of Gd-DTPA. On days 3 and 8, after the injection of ultrasmall superparamagnetic iron oxide (USPIO), T2*- and T2-mapping images were acquired. The R2 values of ME, IMH, MI, and remote areas were measured. Results From days 2 to 3, R2 values increased in the IMH, MI, ME, and remote area (all P < 0.05) following administration of USPIO, while the delta R2 value of IMH and MI was larger than remote area (P < 0.05). From day 7 to day 8, there was no significant difference in the IMH, MI, ME, and remote area (all P > 0.05). Conclusion Microvascular injury of IMH and MI is the most severe among all the studied myocardial injuries in the early reperfusion of MI, while microvascular density decreased during follow-up.