Miracle-dz/UniFAR-FTUs huggingface dataset:
Biofabrication of an in-vitro bone model for Gaucher disease

Gaucher disease (GD), the most prevalent lysosomal disorder, is caused by GBA1 gene mutations, leading to deficiency of glucocerebrosidase, and accumulation of glycosphingolipids in cells of the mononuclear phagocyte system. While skeletal diseases are the leading cause of morbidity and reduced quality of life in GD, the pathophysiology of bone involvement is not yet fully understood, partly due to lack of relevant human model systems. In this work, we present the first 3D human model of GD using aspiration-assisted freeform bioprinting, which enables a platform tool with a potential for decoding the cellular basis of the developmental bone abnormalities in GD. In this regard, human bone marrow-derived mesenchymal stem cells (obtained commercially) and peripheral blood mononuclear cells derived from a cohort of GD patients, at different severities, were co-cultured to form spheroids and differentiated into osteoblast and osteoclast lineages, respectively. Co-differentiated spheroids were then 3D bioprinted into rectangular tissue patches as a bone tissue model for GD. The results revealed positive alkaline phosphatase (ALP) and tartrate-resistant ALP activities, with multi-nucleated cells demonstrating the efficacy of the model, corroborating with gene expression studies. There were no significant changes in differentiation to osteogenic cells but pronounced morphological deformities in spheroid formation, more evident in the ‘severe’ cohort, were observed. Overall, the presented GD model has the potential to be adapted to personalized medicine not only for understanding the GD pathophysiology but also for personalized drug screening and development.
Oxytetracycline-resistant Paenibacillus larvae identified in commercial beekeeping operations in Saskatchewan using pooled honey sampling

American foulbrood (AFB) is an infectious disease of honey bee brood caused by the endospore-forming bacterium Paenibacillus larvae. P. larvae spores are resilient in the environment, thus colonies with clinical signs of AFB are often destroyed by burning to eradicate the causative agent. To prevent outbreaks of AFB, oxytetracycline metaphylaxis is widely used in North America, resulting in sustained selective pressure for oxytetracycline resistance in P. larvae. To determine if antimicrobial resistance (AMR) is present among P. larvae isolates from commercial beekeeping operations in Saskatchewan, Canada, we performed antimicrobial susceptibility testing of 718 P. larvae samples cultured from pooled, extracted honey collected from 52 beekeepers over a 2-y period, 2019 and 2020. We found that 65 of 718 (9%) P. larvae samples collected from 8 beekeepers were resistant to oxytetracycline with minimum inhibitory concentration (MIC) values of 64–256 µg/mL. Eight of 718 (1%) samples from 4 beekeepers had intermediate resistance to oxytetracycline (MIC: 4–8 µg/mL). Susceptibility testing for tylosin and lincomycin indicated that P. larvae in Saskatchewan continue to be susceptible to these antimicrobials (tylosin MIC: <1 µg/mL, lincomycin MIC: ≤2 µg/mL). Most oxytetracycline-resistant P. larvae samples were identified in northeastern Saskatchewan. Whole-genome sequence analysis identified the P. larvae–specific plasmid pMA67 with tetracycline-resistance gene tet(L) in 9 of 11 oxytetracycline-resistant P. larvae isolates sequenced. Our results highlight the advantage of using pooled, extracted honey as a surveillance tool for monitoring AMR in P. larvae.
Accelerometer Metrics: Healthy Adult Reference Values, Associations with Cardiorespiratory Fitness, and Clinical Implications

ABSTRACT Purpose Accelerometer-assessed physical activity (PA) can be summarized using cut-point–free or population-specific cut-point–based outcomes. We aimed to 1) examine the interrelationship between cut-point–free (intensity gradient (IG) and average acceleration (AvAcc)) and cut-point–based accelerometer metrics, 2) compare the association between cardiorespiratory fitness (CRF) and cut-point–free metrics to that with cut-point–based metrics in healthy adults aged 20 to 89 yr and patients with heart failure, and 3) provide age-, sex-, and CRF-related reference values for healthy adults. Methods In the COmPLETE study, 463 healthy adults and 67 patients with heart failure wore GENEActiv accelerometers on their nondominant wrist and underwent cardiopulmonary exercise testing. Cut-point–free (IG: distribution of intensity of activity across the day; AvAcc: proxy of volume of activity) and traditional (moderate-to-vigorous and vigorous activity) metrics were generated. The “interpretablePA” R-package was developed to translate findings into clinical practice. Results IG and AvAcc yield complementary information on PA with both IG (P = 0.009) and AvAcc (P < 0.001) independently associated with CRF in healthy individuals (adjusted R2 = 73.9%). Only IG was independently associated with CRF in patients with heart failure (P = 0.043, adjusted R2 = 38.4%). The best cut-point–free and cut-point–based model had similar predictive value for CRF in both cohorts. We produced age- and sex-specific reference values and percentile curves for IG, AvAcc, moderate-to-vigorous PA, and vigorous PA for healthy adults. Conclusions IG and AvAcc are strongly associated with CRF and thus indirectly with the risk of noncommunicable diseases and mortality, in healthy adults and patients with heart failure. However, unlike cut-point–based metrics, IG and AvAcc are comparable across populations. Our reference values provide a healthy age- and sex-specific comparison that may enhance the translation and utility of cut-point–free metrics in clinical practice.
Case series of intestinal microsporidiosis in non-HIV patients caused by Encephalitozoon hellem

ABSTRACT Intestinal microsporidiosis is most often caused by Enterocytozoon bieneusi, and to a lesser extent by species of the genus Encephalitozoon. Until now, Encephalitozoon hellem was not clearly known to induce disease restricted to the intestine, or rarely in HIV subjects or in tropical countries. We report here 11 cases of delineated intestinal microsporidioses due to E. hellem diagnosed in France in non-HIV patients. Briefly, all patients were immunocompromised. They all suffered from diarrhoea, associated in nearly 50% of cases with weight loss. Concerning treatment, 5/11 patients had a discontinuation or a decrease of their immunosuppressive therapy, and 4/11 received albendazole. All patients recovered. Five different genotypes were identified based on the rRNA ITS sequence.
An Early Neoplasia Index (ENI10), Based on Molecular Identity of CD10 Cells and Associated Stemness Biomarkers, is a Predictor of Patient Outcome in Many Cancers

An accurate estimate of patient survival at diagnosis is critical to plan efficient therapeutic options. A simple and multiapplication tool is needed to move forward the precision medicine era. Taking advantage of the broad and high CD10 expression in stem and cancers cells, we evaluated the molecular identity of aggressive cancer cells. We used epithelial primary cells and developed a breast cancer stem cell–based progressive model. The superiority of the early-transformed isolated molecular index was evaluated by large-scale analysis in solid cancers. BMP2-driven cell transformation increases CD10 expression which preserves stemness properties. Our model identified a unique set of 159 genes enriched in G2–M cell-cycle phases and spindle assembly complex. Using samples predisposed to transformation, we confirmed the value of an early neoplasia index associated to CD10 (ENI10) to discriminate premalignant status of a human tissue. Using a stratified Cox model, a large-scale analysis (>10,000 samples, The Cancer Genome Atlas Pan-Cancer) validated a strong risk gradient (HRs reaching HR = 5.15; 95% confidence interval: 4.00–6.64) for high ENI10 levels. Through different databases, Cox regression model analyses highlighted an association between ENI10 and poor progression-free intervals for more than 50% of cancer subtypes tested, and the potential of ENI10 to predict drug efficacy. The ENI10 index constitutes a robust tool to detect pretransformed tissues and identify high-risk patients at diagnosis. Owing to its biological link with refractory cancer stem cells, the ENI10 index constitutes a unique way of identifying effective treatments to improve clinical care. Significance: We identified a molecular signature called ENI10 which, owing to its biological link with stem cell properties, predicts patient outcome and drugs efficiency in breast and several other cancers. ENI10 should allow early and optimized clinical management of a broad number of cancers, regardless of the stage of tumor progression.
Great expectations and hard times : The ( nontrivial ) impact of education on domestic terrorism

This contribution investigates the role of education in domestic terrorism for 133 countries between 1984 and 2007. The findings point at a nontrivial effect of education on terrorism. Lower education (primary education) tends to promote terrorism in a cluster of countries where the socioeconomic, political and demographic conditions are unfavorable, while higher education (university education) reduces terrorism in a cluster of countries where conditions are more favorable. This suggests that country-specific circumstances mediate the effect of education on the (opportunity) costs and benefits of terrorism. For instance, the prevalence of poor structural conditions in combination with advances in education may explain past and present waves of terrorism and political instability in the Middle East. The results of this study imply that promoting education needs to be accompanied by sound structural change so that it can positively interact with (individual and social) development, thereby reducing terrorism. JEL-Code: D740, I210, I250.
Refuge‐yeah or refuge‐nah? Predicting locations of forest resistance and recruitment in a fiery world

Climate warming, land use change, and altered fire regimes are driving ecological transformations that can have critical effects on Earth's biota. Fire refugia—locations that are burned less frequently or severely than their surroundings—may act as sites of relative stability during this period of rapid change by being resistant to fire and supporting post‐fire recovery in adjacent areas. Because of their value to forest ecosystem persistence, there is an urgent need to anticipate where refugia are most likely to be found and where they align with environmental conditions that support post‐fire tree recruitment. Using biophysical predictors and patterns of burn severity from 1180 recent fire events, we mapped the locations of potential fire refugia across upland conifer forests in the southwestern United States (US) (99,428 km2 of forest area), a region that is highly vulnerable to fire‐driven transformation. We found that low pre‐fire forest cover, flat slopes or topographic concavities, moderate weather conditions, spring‐season burning, and areas affected by low‐ to moderate‐severity fire within the previous 15 years were most commonly associated with refugia. Based on current (i.e., 2021) conditions, we predicted that 67.6% and 18.1% of conifer forests in our study area would contain refugia under moderate and extreme fire weather, respectively. However, potential refugia were 36.4% (moderate weather) and 31.2% (extreme weather) more common across forests that experienced recent fires, supporting the increased use of prescribed and resource objective fires during moderate weather conditions to promote fire‐resistant landscapes. When overlaid with models of tree recruitment, 23.2% (moderate weather) and 6.4% (extreme weather) of forests were classified as refugia with a high potential to support post‐fire recruitment in the surrounding landscape. These locations may be disproportionately valuable for ecosystem sustainability, providing habitat for fire‐sensitive species and maintaining forest persistence in an increasingly fire‐prone world.
TLR-MEDIATED SUPPRESSION OF THE CCL22-CCR4 AXIS AS A NEW TARGET FOR TUMOR IMMUNOTHERAPY

binders (both CTA-derived and mutation-derived peptides) in the homozygous cohort. Our findings demonstrate a reduced amount of potentially immunogenic peptides in EGA patients with HLA-homozygosity for at least one locus, which may result in impaired cancer immunosurveillance. In line with this observation, we also found increased levels of CTA expression in homozygous compared to heterozygous patients. After artificial modification of the genotype of homozygous patients to a heterozygous genotype, the set of predicted good-binding peptides was comparable to the heterozygous cohort.
Burden, risk factors and outcomes associated with adequately treated hypothyroidism in a population-based cohort of pregnant women from North India

Hypothyroidism is the commonest endocrine disorder of pregnancy, with known adverse feto-maternal outcomes. There is limited data on population-based prevalence, risk factors and outcomes associated with treatment of hypothyroidism in early pregnancy. We conducted analysis on data from an urban and peri-urban low to mid socioeconomic population-based cohort of pregnant women in North Delhi, India to ascertain the burden, risk factors and impact of treatment, on adverse pregnancy outcomes- low birth weight, prematurity, small for gestational age and stillbirth. This is an observational study embedded within the intervention group of the Women and Infants Integrated Interventions for Growth Study, an individually randomized factorial design trial. Thyroid stimulating hormone was tested in 2317 women in early (9–13 weeks) pregnancy, and thyroxin replacement started hypothyroid (TSH ≥2.5mIU/mL). Univariable and multivariable generalized linear model with binomial family and log link were performed to ascertain risk factors associated with hypothyroidism and association between hypothyroidism and adverse pregnancy outcomes. Of 2317 women, 29.2% (95% CI: 27.4 to 31.1) had hypothyroidism and were started on thyroxin replacement with close monitoring. Overweight or obesity was associated with increased risk (adjusted RR 1.29, 95% CI 1.10 to 1.51), while higher hemoglobin concentration was associated with decreased risk (adjusted RR 0.93, 95% CI 0.88 to 0.98 for each g/dL) for hypothyroidism. Hypothyroid women received appropriate treatment with no increase in adverse pregnancy outcomes. Almost a third of women from low to mid socio-economic population had hypothyroidism in early pregnancy, more so if anemic and overweight or obese. With early screening and adequate replacement, adverse pregnancy outcomes may be avoided. These findings highlight the need in early pregnancy for universal TSH screening and adequate treatment of hypothyroidism; as well as for attempts to reduce pre and peri-conception overweight, obesity and anemia. Clinical trial registration: Clinical trial registration of Women and Infants Integrated Interventions for Growth Study Clinical Trial Registry–India, #CTRI/2017/06/008908; Registered on: 23/06/2017, (http://ctri.nic.in/Clinicaltrials/pmaindet2.php? trialid=19339&EncHid=&userName=society%20for%20applied%20studies).
Examining the Structure of the Leisure Involvement/Place Bonding Relationship in Three Sumter National Forest Camping Areas

Recreation places often take on significant meaning for people for a plethora of reasons. Leisure literature has begun to examine the way that people’s leisure involvement may impact their attachment to places. The purpose of this investigation was to examine the relationship between the dimensions of leisure involvement and the dimensions of place bonding among a sample of recreationists camping in three camping areas in a southeastern National Forest. Four hundred twenty four campers (83% response) in the Sumter National Forest in South Carolina were surveyed to examine the leisure involvementàplace bonding relationship. Using multidimensional conceptualizations of both constructs, our results indicated that leisure involvement was a positive predictor of recreationists attachment to the forest.
A novel risk variant block across introns 36–45 of CACNA1C for schizophrenia: a cohort-wise replication and cerebral region-wide validation study

Objectives Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. Methods We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. Results A novel 17-variant block across introns 36–45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 × 10−4 ≤ P ≤ 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 × 10−3 ≤ P ≤ 0.050), GMVs of subcortical structures (0.016 ≤ P ≤ 0.048), cortical surface areas (0.010 ≤ P ≤ 0.050), and thickness (0.004 ≤ P ≤ 0.050) in multiple brain regions. Conclusion We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia.
Tziavos, NI, Gkantou, M, Theofanous, M, Dirar, S and Baniotopoulos, C Behaviour of grout-filled double-skin tubular steel stub-columns: Numerical modelling and design considerations

47 The use of grout-filled double-skin tubular (GFDST) sections in civil, bridge and offshore engineering 48 applications is rapidly increasing. The design of such composite members is not directly covered by 49 design codes, despite recent research studies investigating their performance, proposing design 50 equations or modifying existing codified methods. Aiming to extend the available pool of structural 51 performance data, the current study reports the results of an extensive numerical investigation on 52 GFDST stub-columns. Finite element (FE) models, are developed and validated against published test 53 data. A parametric investigation is conducted to evaluate the effect of key parameters, including cross-54 sectional slenderness, hollow ratio and the effect of concrete infill on the capacity of GFDST members. 55 The numerically obtained load capacities along with collated test data are utilised to assess the 56 applicability of design strength predictions based on European Code (EC4), the American Concrete 57 Institute (ACI) and the analytical models proposed by Han et al. and Yu et al. Overall, the modified Yu 58 et al. provided strength predictions with low scatter, whereas ACI yielded overly conservative 59 predictions particularly for smaller hollow ratios.
Preliminary Guidelines for Replacing Word-Recognition in Quiet With Speech in Noise Assessment in the Routine Audiologic Test Battery

Objectives: For decades, monosyllabic word-recognition in quiet (WRQ) has been the default test of speech recognition in routine audiologic assessment. The continued use of WRQ scores is noteworthy in part because difficulties understanding speech in noise (SIN) is perhaps the most common complaint of individuals with hearing loss. The easiest way to integrate SIN measures into routine clinical practice would be for SIN to replace WRQ assessment as the primary test of speech perception. To facilitate this goal, we predicted classifications of WRQ scores from the QuickSIN signal to noise ratio (SNR) loss and hearing thresholds. Design: We examined data from 5808 patients who underwent audiometric assessment at the Stanford Ear Institute. All individuals completed pure-tone audiometry, and speech assessment consisting of monaural WRQ, and monaural QuickSIN. We then performed multiple-logistic regression to determine whether classification of WRQ scores could be predicted from pure-tone thresholds and QuickSIN SNR losses. Results: Many patients displayed significant challenges on the QuickSIN despite having excellent WRQ scores. Performance on both measures decreased with hearing loss. However, decrements in performance were observed with less hearing loss for the QuickSIN than for WRQ. Most important, we demonstrate that classification of good or excellent word-recognition scores in quiet can be predicted with high accuracy by the high-frequency pure-tone average and the QuickSIN SNR loss. Conclusions: Taken together, these data suggest that SIN measures provide more information than WRQ. More important, the predictive power of our model suggests that SIN can replace WRQ in most instances, by providing guidelines as to when performance in quiet is likely to be excellent and does not need to be measured. Making this subtle, but profound shift to clinical practice would enable routine audiometric testing to be more sensitive to patient concerns, and may benefit both clinicians and researchers.
Evidence2Practice (E2P): Leveraging Implementation Science to Promote Careers in HIV Research Among Students From Historically Black Colleges and Universities

Supplemental Digital Content is Available in the Text. Background: The HIV research workforce is not representative of populations most affected by the epidemic. Innovative educational programs are needed to motivate diverse student populations to pursue careers in HIV research. Methods: The Duke University Center for AIDS Research Evidence2Practice (E2P) program is a 3-day interactive workshop that introduces students from Historically Black Colleges and Universities (HBCU) to HIV pre-exposure prophylaxis, implementation science, and human-centered design. Participants develop 1-page action plans to increase awareness and uptake of pre-exposure prophylaxis on their campus. The program was evaluated using a partially mixed-method concurrent equal status study design with pre-program and post-program surveys and in-depth interviews. Results: Among the 52 participating students, 44 completed the preworkshop survey, 45 completed the postworkshop survey, and 10 participated in an in-depth interview. Most participants identified as Black or African American and cisgender female. Participating in the E2P program was associated with: (1) an increase in median interest in pursuing a career in HIV research (P < 0.01) and (2) a decrease in median perceived difficulty in starting a career in HIV research (P < 0.01). Several students described that a lack of knowledge about initiating an HIV research career, a perceived lack of qualifications and knowledge about HIV science, and limited experience were major barriers to considering careers in HIV research. Conclusions: The E2P program enhanced HBCU students' interest in careers related to HIV research and improved their self-efficacy to pursue such careers. On-campus educational enrichment initiatives, led by active HIV researchers and clinicians, should be a critical part of diversifying the HIV workforce.