Miracle-dz/UniFAR-FTUs huggingface dataset:
Blood‐brain barrier transport using a high affinity, brain‐selective VNAR antibody targeting transferrin receptor 1

Transfer across the blood‐brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. We established a functional selection method to identify high affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB. A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used for in vitro selection against recombinant human TfR1 ectodomain (rh‐TfR1‐ECD) followed by in vivo selection in mouse for brain parenchyma penetrating antibodies. TXB2 VNAR was identified as a high affinity, species cross‐reactive VNAR antibody against TfR1‐ECD that does not compete with transferrin or ferritin for receptor binding. IV dosing of TXB2 when fused to human Fc domain (TXB2‐hFc) at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1‐positive neurons. Likewise, IV dosing of TXB2‐hFc fused with neurotensin (TXB2‐hFc‐NT) at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2‐hFc did not elicit any acute adverse reactions, bind, or deplete circulating reticulocytes or reduce BBB‐expressed endogenous TfR1 in mice. There was no evidence of target‐mediated clearance or accumulation in peripheral organs except lung. In conclusion, TXB2 is a high affinity, species cross‐reactive, and brain‐selective VNAR antibody to TfR1 that rapidly crosses the BBB and exhibits a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.
Simulating the effect of glenohumeral capsulorrhaphy on kinematics and muscle function

This study aimed to use a predictive simulation framework to examine shoulder kinematics, muscular effort, and task performance during functional upper limb movements under simulated selective glenohumeral capsulorrhaphy. A musculoskeletal model of the torso and upper limb was adapted to include passive restraints that simulated the changes in shoulder range of motion stemming from selective glenohumeral capsulorrhaphy procedures (anteroinferior, anterosuperior, posteroinferior, posterosuperior, and total anterior, inferior, posterior, and superior). Predictive muscle‐driven simulations of three functional movements (upward reach, forward reach, and head touch) were generated with each model. Shoulder kinematics (elevation, elevation plane, and axial rotation), muscle cost (i.e., muscular effort), and task performance time were compared to a baseline model to assess the impact of the capsulorrhaphy procedures. Minimal differences in shoulder kinematics and task performance times were observed, suggesting that task performance could be maintained across the capsulorrhaphy conditions. Increased muscle cost was observed under the selective capsulorrhaphy conditions, however this was dependent on the task and capsulorrhaphy condition. Larger increases in muscle cost were observed under the capsulorrhaphy conditions that incurred the greatest reductions in shoulder range of motion (i.e., total inferior, total anterior, anteroinferior, and total posterior conditions) and during tasks that required shoulder kinematics closer to end range of motion (i.e., upward reach and head touch). The elevated muscle loading observed could present a risk to joint capsule repair. Appropriate rehabilitation following glenohumeral capsulorrhaphy is required to account for the elevated demands placed on muscles, particularly when a significant range of motion loss presents.
Hikikomori Risk Inventory (HRI-24): A new instrument for evaluating Hikikomori in both Eastern and Western countries

Background: Hikikomori, a clinical condition widely studied in Japan, is receiving increasing attention in Western Countries. Aims: This study aimed to create a new instrument for evaluating the risk of Hikikomori in both Eastern and Western countries. Methods: Through two studies on Italian adolescents, youths, and adults (n = 1,285) and a study on Japanese youths and adults (n = 392), we analyzed the psychometric properties of the Hikikomori Risk Inventory (HRI-24). Results: We found support, in both the Italian and Japanese samples, for the good and stable factor structure of the scale (CFI = 0.94, RMSEA = 0.057 for both the adult samples), as well as for its convergent and divergent validity. Conclusions: The HRI-24 might be used in future studies in both Western and Eastern countries to shed light on the features of this clinical disorder in different cultures. This will allow the development of culture-sensitive preventive and clinical interventions.
Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers

Programmed Death Ligand 1 (PD-L1) positivity rates differ between different metastatic sites and the primary tumor. Understanding PD-L1 expression characteristics could guide biopsy procedures and motivate research to better understand site-specific differences in the tumor microenvironment. The purpose of this study was to compare PD-L1 positivity on immune cells and tumor cells in primary and metastatic triple negative breast cancer (TNBC) tumors. Retrospective study utilizing the PD-L1 database of Foundation Medicine containing the SP142 companion diagnostic immunohistochemistry assay (SP142 CDx) and Food and Drug Administration guidelines for scoring. 340 TNBC cases (179 primary tumors and 161 unmatched metastatic lesions) were evaluated. The primary outcome measures were PD-L1 positivity rates in immune cells and tumor cells. χ2 test was used for comparisons. Spearman’s correlation coefficient was used for correlations. More primary tumors were positive for PD-L1 expression on immune cells than metastatic lesions (114 (63.7%) vs 68 (42.2%), p<0.0001). This was driven by the lower PD-L1 positivity rates in skin (23.8%, 95% CI: 8.22% to 47.2%), liver (17.4%, 95% CI: 5.00% to 38.8%) and bone (16.7%, 95% CI: 2.10% to 48.4%) metastases. Lung (68.8%, 95% CI: 41.3% to 90.0%), soft tissues (65.2%, 95% CI: 42.7% to 83.6%) and lymph nodes (51.1%, 95% CI: 35.8% to 66.3%) had PD-L1 % positivity rates similar to primary tumors. PD-L1 expression was rare on tumor cells in both the breast and metastatic sites (8.3% vs 4.3%, p=0.13). The rate of PD-L1 positivity varies by metastatic location with substantially lower positivity rates in liver, skin and bone metastases compared with primary breast lesions or lung, soft tissue or lymph node metastases. This difference in PD-L1 positivity rates between primary tumors and different metastatic sites should inform physicians when choosing sites to biopsy and suggests a difference in the immune microenvironment across metastatic sites.
Hyposalivation, oral health, and Candida colonization in independent dentate elders

Hyposalivation is an important problem in elders and could interfere with several oral functions and microbial ecology. While the number of independent elders who retain more natural teeth increases worldwide, few studies examined hyposalivation in this population. Thus, this study aims to examine relationships between hyposalivation, oral health conditions and oral Candida colonization in independent dentate elders and evaluate factors associated with salivary flow and Candida carriage. We conducted a cross-sectional study in fifty-three dentate elders (≥65 years old with at least 4 pairs of posterior occlusal contacts) with no, or well-controlled, systemic conditions. Participants were interviewed for medical history, subjective dry mouth symptoms, oral hygiene practices and denture information. Unstimulated and stimulated salivary flow rates, objective dry mouth signs, gingival, tongue-coating, and root-caries indices were recorded. Stimulated saliva was cultured on Sabouraud-dextrose agar for Candida counts. Candida species were identified using chromogenic Candida agar and polymerase chain reaction. Statistical significance level was set at p<0.05. The results showed that hyposalivation was associated with higher gingival and tongue-coating indices (p = 0.003 and 0.015, respectively), but not root-caries index. Hyposalivation was also associated with higher prevalence of oral Candida colonization (p = 0.010; adjusted OR = 4.36, 95% confidence interval = 1.29–14.72). These two indices and Candida load were negatively correlated with unstimulated and stimulated salivary flow rates. Interestingly, non-albicans Candida species were more prevalent in denture wearers (p = 0.017). Hence, hyposalivation is a risk factor for poorer oral health and oral Candida colonization in independent dentate elders. Because of its potential adverse effects on oral and systemic health, hyposalivation should be carefully monitored in elders.
Effects of pimobendan on left atrial transport function in cats

Abstract Background Arterial thromboembolism is a sequela of hypertrophic cardiomyopathy (HCM) in cats related to left atrial (LA) enlargement and dysfunction. Hypothesis Pimobendan improves LA transport function in cats. Animals Twenty‐two client‐owned cats with HCM and 11 healthy cats. Methods Prospective, double‐blind, randomized, placebo‐controlled clinical cohort study. Cats were randomized to receive either pimobendan (0.25 mg/kg PO q12h) or placebo for 4 to 7 days. Nineteen echocardiographic variables of LA size and function were evaluated. Statistical comparisons included t tests, analysis of variance, and multivariable analyses. Results Peak velocity of left auricular appendage flow (LAapp peak; mean ± SD, 0.85 ± 0.20 vs 0.71 ± 0.22 m/s; P = .01), maximum LA volume (P = .03), LA total emptying volume (P = .03), peak velocity of late diastolic transmitral flow (A peak velocity; 0.77 ± 0.12 vs 0.62 ± 0.17 m/s; P = .05), and A velocity time integral (A VTI; 3.05 ± 0.69 vs 3.37 ± 0.49; P = .05) were increased after pimobendan. Mean change after pimobendan was larger in cats with HCM compared to healthy cats for LA fractional shortening (2.1% vs −2.1%; P = .05), A VTI (0.58 vs 0.01 cm; P = .01), LAapp peak (0.20 vs 0.02 m/s; P = .02), LA kinetic energy (3.51 vs −0.10 kdynes‐cm; P = .05), and LA ejection force (1.93 vs −0.07 kdynes; P = .01) in the multivariable model. The stronger effect of pimobendan in cats with HCM was independent of LA size. Conclusions and Clinical Importance We identified positive, albeit minor, effects of pimobendan on LA function in cats with HCM. Whether or not treatment with pimobendan decreases the risk of cardiogenic embolism deserves further study.
Volumetric Versus Empirical Determination of Enucleation Implant Size

Purpose: To compare the use of sizing implants versus intraoperative volume measurements for individualization of enucleation implant size, and to identify preoperative factors affecting the choice of implant. Methods: In this retrospective observational cohort study, 2 implant sizing methods were compared using clinical records and photographs in 139 patients who underwent enucleation between 2007 and 2016. Results: There was no difference in mean implant (p = 0.6562) or prosthetic (p = 0.1990) enophthalmos between the 2 methods, or when comparing patients with and without conjunctival-Tenons fibrosis. The incidence and severity of superior sulcus deformity was similar between the methods (p = 0.6394). Preoperative phthisis (p < 0.0001) and intraoperative conjunctival-Tenons fibrosis (p = 0.0010) were more common in the sizing implant group. Among all study patients, mean implant size was larger in males (21.3 mm, n = 80) than females (20.7 mm, n = 59) (p = 0.0027). Implants >20 mm were more frequently inserted in patients with a wider Hertel exophthalmometry base (80% of males >95 mm; 77% of females >97 mm). Approximately 21.0% of patients demonstrated ≥8 mm of implant enophthalmos, suggesting an undersized implant. The authors estimate that 11% of patients could have received a sphere larger than 22 mm. Conclusions: Individualization of enucleation implant size can reduce the incidence of anophthalmic socket syndrome. The empirical use of sizing implants provided similar results as intraoperative volumetric measurements, when evaluated by postoperative superior sulcus depth and prosthetic or implant enophthalmos. Preoperative exophthalmometry may facilitate selection of implant size. Preexisting conjunctival-Tenon fascial fibrosis often did not limit implant size and was not associated with a higher prevalence of wound breakdown or implant exposure. Similar postoperative results were achieved when determining enucleation implant size using sizing implants versus intraoperative volume measurements.
Evidence that investors penalize female founders for lack of industry fit

Female-led ventures are penalized in funding and valuation when catering to male-dominated industries due to a “lack of fit. ” Are female founding CEOs penalized when raising funds for their ventures based on industry served? Across an observational study conducted on ventures seeking funding (N = 392) and an experimental study conducted on investors allocating venture funding (N = 130), we find evidence for a “lack of fit” effect: Female-led ventures catering to male-dominated industries receive significantly less funding at significantly lower valuations than female-led ventures catering to female-dominated industries. In contrast, male-led ventures attain similar funding and valuation outcomes regardless of the gender dominance of the industries to which they cater. We confirm that this is because investors perceive lower degrees of fit between founding CEO and venture for female-led ventures catering to male- as opposed to female-dominated industries (with no perceived fit differences for male-led ventures across industries). Degree of investor sophistication emerges as a potential attenuating factor, appearing to help reduce gender bias from perceived lack of fit.
Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

BACKGROUND The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. METHODS We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). RESULTS Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively). CONCLUSIONS An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.
Soluble Receptor for Advanced Glycation End Products and Its Forms in COVID-19 Patients with and without Diabetes Mellitus: A Pilot Study on Their Role as Disease Biomarkers

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.
Identification of Two Novel Circular RNAs Deriving from BCL2L12 and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer

The utility of circular RNAs (circRNAs) as molecular biomarkers has recently emerged. However, only a handful of them have already been studied in colorectal cancer (CRC). The purpose of this study was to identify new circRNAs deriving from BCL2L12, a member of the BCL2 apoptosis-related family, and investigate their potential as biomarkers in CRC. Total RNA extracts from CRC cell lines and tissue samples were reversely transcribed. By combining PCR with divergent primers and nested PCR followed by Sanger sequencing, we were able to discover two BCL2L12 circRNAs. Subsequently, bioinformatical tools were used to predict the interactions of these circRNAs with microRNAs (miRNAs) and RNA-binding proteins (RBPs). Following a PCR-based pre-amplification, real-time qPCR was carried out for the quantification of each circRNA in CRC samples and cell lines. Biostatistical analysis was used to assess their potential prognostic value in CRC. Both novel BCL2L12 circRNAs likely interact with particular miRNAs and RBPs. Interestingly, circ-BCL2L12-2 expression is inversely associated with TNM stage, while circ-BCL2L12-1 overexpression is associated with shorter overall survival in CRC, particularly among TNM stage II patients. Overall, we identified two novel BCL2L12 circRNAs, one of which can further stratify TNM stage II patients into two subgroups with substantially distinct prognosis.
Sociodemographic Differences in Time Trends of Suicidal Thoughts and Suicide Attempts Among Adolescents Living in Amsterdam, The Netherlands

Abstract. Background: Suicidal thoughts and suicide attempts among adolescents are major public health problems. More insight into secular changes in suicidal thoughts and suicide attempts among adolescents from various sociodemographic groups is crucial for adequate and targeted policy-making and prevention. We therefore examined 5-year time trends in suicidal thoughts and suicide attempts among adolescents and potential differences in time trends between sociodemographic groups. Methods: Logistic regression analyses were based on annually repeated cross-sectional data including 26,273 multi-ethnic students (13–14 years old) in the second year of various levels of secondary education in Amsterdam, The Netherlands. Results: Overall, the prevalence of adolescents in Amsterdam with suicidal thoughts decreased from 17.6% during 2010–2011 to 13.2% during 2014–2015. The prevalence of adolescents reporting suicide attempts decreased from 2.9% to 1.9% over the observed 5-year period. We found differences in these time trends between subgroups based on ethnicity and educational level. Limitations: The use of confidential and self-reported data could have biased the results. Conclusion: In order for prevention policy to be effective it is important to pay attention to changes in risk groups for suicidal thoughts and suicide attempts over time.
Aging in Place With a Spouse in Need: Neighborhood Cohesion and Older Adult Spouses’ Physical and Mental Health

This study examines the association of perceived neighborhood cohesion (NC) with older adults’ health and the buffering effects of NC against the negative effects of spousal caregiving on health. Data of 3329 community-living older adults living with a spouse in need of care from the Health and Retirement Study were collected at two time-points. Multiple regression analyses were computed for each of the four health outcomes. For men, NC predicted fewer depressive symptoms and better cognition. NC buffered the negative effect of providing activities of daily living (ADL) help to the wife on cognition. For women, NC predicted fewer depressive symptoms and better cognition. NC buffered the negative effect of providing ADL help to the husband on ADL difficulties. The results accentuate the importance of residency location for older adults’ physical and mental health. The health benefits of NC may have more implications for older adults providing spousal care.
Questioning coverage values determined by 2D western blots: A critical study on the characterization of anti‐HCP ELISA reagents

Host cell proteins (HCPs) constitute a major class of process‐related impurities, whose substantial clearance must be demonstrated by suitable analytical methods to warrant product quality and reduce potential safety risks for patients. In this regard, enzyme linked immunosorbent assays (ELISAs), which primarily rely on the quality of the HCP reference standard (immunogen) and HCP‐specific polyclonal antibodies, are considered the gold standard for HCP monitoring. For the qualification of the employed antibodies, two‐dimensional (2D) western blots (2D‐WBs) are the preferred technique to determine the coverage, though a number of practical constraints are well recognized. By using several orthogonal approaches, such as affinity‐based mass spectrometry and indirect ELISA, the present study revealed potential detection gaps (i.e., noncovered HCPs) of conventional 2D‐WBs, which can be primarily attributed to two different root causes: (i) low amounts of proteins or antibodies being unable to overcome the detection limit and (ii) western blot artifacts due to the loss of conformational epitopes through protein denaturation hindering HCP‐antibody recognition. In contrast, the lack of specific antibodies against certain (particularly, low molecular weight) HCPs, as proposed in previous studies, seems to play only a minor role. Together, these findings imply that CHO‐HCP ELISA antibodies are better than qualification studies by 2D‐WBs indicate.