bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first‐in‐human study
Authors: Gao Lan , Bhattacharyya Anuradha , Beers Brian , Kaushik Diksha , Bredlau Amy‐Lee , Kristensen Allan , Abd‐Elaziz Khalid , Grant Richard , Golden Lee , Kong Ronald 
Published: August 2024

AbstractAimsPTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre‐mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease‐modifying treatments. This first‐in‐human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.MethodsThis phase 1, single‐centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects.ResultsPTC518 demonstrated a favourable safety profile. The majority of treatment‐emergent adverse events were mild and transient. PTC518 Tmax was reached at 6–7 h and the terminal T1/2 was 54.0–75.3 h following a single oral dose. Exposure increased with dose though less than dose proportionally. The PTC518 concentrations in cerebrospinal fluid were approximately 2.6‐fold higher than the unbound free‐drug concentrations in plasma. A significant dose‐dependent reduction of up to approximately 60% in HTT mRNA and a significant dose‐dependent, time‐dependent and sustained reduction in HTT protein levels of up to 35% were observed after PTC518 treatment.ConclusionsPTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose‐dependent decrease in systemic HTT mRNA and HTT protein levels. Results from this first‐in‐human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD.
Beta‐thalassaemia intermedia due to a complex alpha‐globin rearrangement and a heterozygous beta thalassaemia mutation
Authors: Marin Victor , Huguenin Yoann , Bessi Lucile , Weinmann Laurent , Augis Vanessa , Desclaux Arnaud , Lebreton Louis , Dulucq Stephanie , Boutin Julian 
Published: August 2024

SummaryThe alpha‐thalassaemia alleles are very frequent in the world's population. The main molecular mechanism is a large deletion with the loss of one or two alpha genes. Another type of rarer abnormality exists: the gain of alpha genes. The consequence of a gain is an overproduction of alpha‐globin chains, which aggravates a beta‐thalassaemia trait into an intermedia phenotype (non‐transfusion‐dependent thalassaemia, NTDT). Here, we report the case of a young girl referred for a beta‐NTDT with a combination never described in the literature: a heterozygous beta‐thalassaemia mutation associated with a copy number gain of the alpha‐globin locus and ‐alpha 3.7 deletion on the same allele.
Item reduction of the “Support Intensity Scale” for people with intellectual disabilities, using machine learning
Authors: González‐Carrasco Félix , Espinosa Parra Felipe , Álvarez‐Aguado Izaskun , Ponce Olguín Sebastián , Vega Córdova Vanessa , Roselló‐Peñaloza Miguel 
Published: August 2024

AbstractBackgroundThe study focuses on the need to optimise assessment scales for support needs in individuals with intellectual and developmental disabilities. Current scales are often lengthy and redundant, leading to exhaustion and response burden. The goal is to use machine learning techniques, specifically item‐reduction methods and selection algorithms, to develop shorter and more efficient scales.MethodsA data set of 93 participants was analysed using the Supports Needs Scale. Five feature‐selection algorithms were evaluated to create a shortened questionnaire. For each algorithm, a Random Forest model was trained, and performance was assessed using metrics like accuracy, precision, recall and F1‐score to measure how well each model predicted support needs.FindingsThe "Select from Model" algorithm successfully identified key items that could predict the level of Support Needs using the Random Forest model. Only 51 variables, out of the original 147, were needed to maintain predictive accuracy. The reduced questionnaire maintained good reliability and internal consistency compared to the original instrument, with a strong F1 score indicating excellent predictive performance.ConclusionsThe study demonstrates that machine learning techniques are effective in reducing the length of support needs questionnaires while preserving their psychometric properties. These methods can help institutions provide more efficient access to information about support needs without compromising validity or reliability, potentially leading to better resource allocation and improved care for individuals with intellectual disabilities.
The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial
Authors: Yu Hongtao , Greasley Peter J. , Lambers Heerspink Hiddo J. , Ambery Philip , Ahlstrom Christine , Hamren Bengt , Khan Anis A. , Boulton David W. , Hallow K. Melissa 
Published: August 2024

AbstractBackground and PurposeEndothelin‐1 (ET‐1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging.ApproachWe utilized a previously developed mathematical model of ET‐1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR).Background and Key ResultsAn effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR.Conclusions and ImpactThese findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.
Visual morbidity in macroprolactinoma: A retrospective cohort study
Authors: Rudman Yaron , Duskin‐Bitan Hadar , Masri‐Iraqi Hiba , Akirov Amit , Shimon Ilan 
Published: August 2024

AbstractObjectiveThe management of visual field damage in patients with macroprolactinomas is a major therapeutic challenge. We aimed to study the visual morbidity associated with macroprolactinoma and its outcomes following medical and surgical treatment. We aimed to identify predictors of visual recovery.MethodsWe retrospectively reviewed patient's data including clinical presentation, serial pituitary magnetic resonance imaging, laboratory tests, visual symptoms and neuro‐ophthalmologic examination, visual field tests and optical coherence tomography tests. The main outcome was complete visual field recovery. Descriptive analyses were conducted. Predictors of visual recovery were investigated.PatientsThe study cohort included 150 patients with macroprolactinoma [median follow‐up, 6.0 years (interquartile range (IQR) 2.9–10.6)].ResultsAt diagnosis, visual field defects were evident in 40 patients (26.7%). At the end of follow‐up, 24 out of 39 available visual field tests (61.5%) exhibited complete recovery. Patients that achieved complete visual recovery had smaller macroadenomas at diagnosis [30.5 mm (15.0–80.0) vs. 42.0 mm (30.0–85.0), p < .01], lower baseline serum prolactin levels [1414 mcg/L (489–3586) vs. 4119 mcg/L (2715–6315), p < .01], lower rates of central hypogonadism (78.3% vs. 93.3%, p = .05) and central hypothyroidism (20.8% vs. 53.3%, p = .04), lower rates of compressive optic neuropathy (35.3% vs. 87.5%, p = .02) and a better visual acuity (better than 6/8 in both eyes, 93.7% vs. 28.6%, p < .01).ConclusionsIn our cohort of 150 patients with macroprolactinoma, 40 patients (26.7%) presented with visual field defects, of which 61.5% achieved complete visual recovery with treatment. Patients that achieved complete visual recovery presented with smaller macroadenomas, lower serum prolactin levels, lower rates of central hypogonadism and central hypothyroidism, lower rates of compressive optic neuropathy and better visual acuity.
Safflower Alleviates Pulmonary Arterial Hypertension by Inactivating NLRP3: A Combined Approach of Network Pharmacology and Experimental Verification
Authors: Ding Shibiao , Cui Jinyu , Yan Luning , Ru Chuhui , He Fei , Chen Aifeng 
Published: August 2024

ABSTRACTIntroductionTraditional Chinese medicinal plant, safflower, shows effective for treating pulmonary arterial hypertension (PAH), yet the underlying mechanisms remain largely unexplored. This study is aimed at exploring the potential molecular mechanisms of safflower in the treatment of PAH.MethodsNetwork pharmacology approach and molecular docking were applied to identify the core active compounds, therapeutic targets, and potential signaling pathways of safflower against PAH. Meanwhile, high‐performance liquid chromatography (HPLC) assay was performed to determine the core compounds from safflower. Further, the mechanism of action of safflower on PAH was verified by in vivo and in vitro experiments.ResultsA total of 15 active compounds and 177 targets were screened from safflower against PAH. Enrichment analysis indicated that these therapeutic targets were mainly involved in multiple key pathways, such as TNF signaling pathway and Th17 cell differentiation. Notably, molecular docking revealed that quercetin (core compound in safflower) displayed highest binding capacity with NLRP3. In vivo, safflower exerted therapeutic effects on PAH by inhibiting right ventricular hypertrophy, inflammatory factor release, and pulmonary vascular remodeling. Mechanistically, it significantly reduced the expression of proangiogenesis‐related factors (MMP‐2, MMP‐9, Collagen 1, and Collagen 3) and NLRP3 inflammasome components (NLRP3, ASC, and Caspase‐1) in PAH model. Similarly, these results were observed in vitro. Besides, we further confirmed that NLRP3 inhibitor had the same therapeutic effect as safflower in vitro.ConclusionOur findings suggest that safflower mitigates PAH primarily by inhibiting NLRP3 inflammasome activation. This provides novel insights into the potential use of safflower as an alternative therapeutic approach for PAH.
Prospective Cohort Study Examining the Ability of Performance‐Based and Self‐Reported Frailty Measures to Predict 30‐Day Rehospitalizations After Kidney Transplantation
Authors: Lorenz Elizabeth C. , Smith Byron H. , Mour Girish , Wadei Hani M. , Kennedy Cassie C. , Schinstock Carrie A. , Kremers Walter K. , Cheville Andrea L. , LeBrasseur Nathan K. , Rule Andrew D. 
Published: August 2024

ABSTRACTPerformance‐based measures of frailty are associated with healthcare utilization after kidney transplantation (KT) but require in‐person assessment. A promising alternative is self‐reported frailty. The goal of this study was to examine the ability of performance‐based and self‐reported frailty measures to predict 30‐day rehospitalizations after KT. We conducted a prospective, observational cohort study involving 272 adults undergoing KT at Mayo Clinic in Minnesota, Florida, or Arizona. We simultaneously measured frailty before KT using the physical frailty phenotype (PFP), the short physical performance battery (SPPB), and self‐report (the Patient‐Reported Outcomes Measurement Information System [PROMIS] 4‐item physical function short form v2.0). Both the PFP and self‐reported frailty were independently associated with more than a 2‐fold greater odds of 30‐day rehospitalizations, while the SPPB was not. To our knowledge, this is the first study to assess the prognostic value of all three of the above frailty measures in patients undergoing KT. The PFP is more prognostic than the SPPB when assessing the risk of 30‐day rehospitalizations; self‐reported frailty can complement the PFP but not replace it. However, the 4‐item survey assessing self‐reported frailty represents a simple way to identify patients undergoing KT surgery who would benefit from interventions to lower the risk of rehospitalizations.
Serum β2‐Microglobulin Predicts Time to Recovery of Delayed Graft Function in Kidney Transplant Recipients
Authors: Parajuli Sandesh , Bloom Margaret , Mandelbrot Didier , Astor Brad C. 
Published: August 2024

ABSTRACTBackgroundDelayed graft function (DGF) after kidney transplantation is associated with adverse patients and allograft outcomes. A longer duration of DGF is predictive of worse graft outcomes compared to a shorter duration. Posttransplant serum β2‐microglobulin (B2M) is associated with long‐term graft outcomes, but its relationship with DGF recovery is unknown.MethodsWe included all kidney‐only transplant recipients with DGF enrolled in the E‐DGF trial. Duration of DGF was defined as the interval between the transplant and the last dialysis session. We analyzed the association of standardized serum creatinine (Scr) and B2M on postoperative Days (POD) 1–7 during the subsequent days of DGF with the recovery of DGF.ResultsA total of 97 recipients with DGF were included. The mean duration of DGF was 11.0 ± 11.2 days. Higher Scr was not associated with the duration of DGF in unadjusted or adjusted models. Higher standardized B2M, in contrast, was associated with a prolonged duration of DGF. This association remained in models adjusting for baseline characteristics from POD 2 (3.19 days longer, 95% CI: 0.46–5.93; p = 0.02) through Day 6 of DGF (4.97 days longer, 95% CI: 0.75–9.20; p = 0.02). There was minimal change in mean Scr (0.01 ± 0. 10 mg/dL per day; p = 0.32), while B2M significantly decreased as the time to recovery approached (–0.14 ± 0.05 mg/L per day; p = 0.006), among recipients with DGF.ConclusionB2M is more strongly associated with DGF recovery than Scr. Posttransplant B2M may be an important biomarker to monitor during DGF.Trial Registration: ClinicalTrials.gov identifier: NCT 03864926
Clinical profiles of people enrolling in alcohol and other drug treatment in Australia: Do youth differ from young adults and adults?
Authors: Campbell Gabrielle , Pocuca Nina , Newland Grace , Ellem Rhiannon , Glasgow Sophia , Dignan Julie , Stokes Holly , Hides Leanne 
Published: August 2024

AbstractIntroductionTo examine and compare age groups on socio‐demographic, substance use, mental health, social and risk behaviour profiles of people entering alcohol and other drug (AOD) treatment in a large non‐government organisation (NGO) in Queensland and New South Wales, Australia.MethodsDesign—Cross‐sectional study; analysis of baseline routine outcome measures (ROM) and AOD minimum datasets for drug and alcohol treatment services. Setting and participants—People enrolling in Lives Lived Well, a large NGO AOD service between November 2020 and October 2022. Main outcome measures—Socio‐demographic, substance use, mental health, social factors and risk behaviours, by youth (≤24 years), young adults (25–35 years) and adults (>35 years).ResultsBetween November 2020 and October 2022, 9413 clients enrolled in Lives Lived Well (LLW) AOD services and completed baseline ROMs. Over one‐fifth (21.9%) were youth (n = 2066), one‐third (32.4%) were young adults (n = 3052) and just under half (45.6%) were adults >35 years (n = 4295). The most common primary drug of concern was cannabis for youth, methamphetamine for young adults and alcohol for adults >35 years. Nearly two‐thirds (61.3%) reported moderate to severe symptoms of depression and 55.0% reported moderate to severe anxiety. Just under half (47.2%) screened positive for PTSD and two‐in‐five (40.4%) reported recent suicidal ideation. Co‐occurring mental health symptoms were more common in youth compared with young adults and adults >35 years.Discussion and ConclusionsCo‐occurring mental health symptoms were high in the sample, particularly among youth. All age groups present with unique and complex socio‐demographic and clinical profiles that are important to understand to provide the most appropriate and effective treatment.
Education and the Timing of Family Formation: Evidence from Quantile Regression Analysis
Authors: Batyra Ewa 
Published: August 2024

ABSTRACTThe relationship between educational level and the age at which women start families has been extensively researched. However, studies have primarily explored how additional schooling shifts the mean or, more broadly, only one point of the age at first union and first birth distributions. This ignores variation in the association between education and the timing of family formation, and the fact that schooling might shape behaviours of vulnerable and more privileged women differently. Using quantile regressions, this article examines heterogeneity in the relationship between education and the age at first union and first birth across the distribution of these events within 50 low‐ and middle‐income countries. It investigates whether additional schooling shifts relatively early union formation and childbearing (that is, lower parts of distributions) similarly or differently than it shifts other parts of the distributions. It finds that association between an additional year at school and the age at first union and birth is weaker in the lower than the upper parts of the distributions. Education has a relatively weak effect on the reduction of early first unions and births and plays an unequalizing role in shaping family formation within countries. These findings are key to understanding persistently high levels of early marriage and pregnancy, despite the expansion of education.
A dyadic investigation of shy children's behavioral and affective responses to delivering a speech
Authors: Hassan Raha , Schmidt Louis A. 
Published: August 2024

AbstractShyness is typically associated with avoidant social behavior and restricted affect in new social situations. However, we know considerably less about how one child's shyness influences another child's behavior and affect in new social situations. Children's shyness was parent‐reported when children were age 3 (N = 105, 52 girls, Mage = 3.50 years), and children were tested approximately 1 year later (Mage = 4.76 years) in same‐gender dyads where they were asked to give an impromptu speech about their most recent birthday in front of an experimenter and the other member of the dyad. We examined whether children's shyness and speech order influenced their own and their social partner's observed behavior and affect during the speech. Regardless of speech order, children's own shyness was positively associated with their own avoidant social behavior and gaze aversion. Regardless of shyness, children who gave their speech second averted their gaze more than children who gave their speech first. We also found that children who gave their speech second displayed less positive affect if their social partner who they watched give the speech first was shyer. We speculate that some 4‐year‐old children may be sensitive to the avoidant behaviors of their shy peers and, in turn, respond with less animation when it is their turn to participate in the same activity.Research Highlights
We examined whether preschool children's shyness and speech order influenced their own and their social partner's observed behavior and affect during a dyadic speech task
Children's own shyness was positively associated with their own avoidant social behavior and gaze aversion
Children who gave their speech second averted their gaze more than children who gave their speech first.
Children who gave their speech second displayed less positive affect if their social partner who they watched give a speech first was shyer
These findings suggest that preschool‐aged children are sensitive to learning about their environment indirectly through social observation
First time ACS in patients with on‐target lipid levels: Inflammation at admission and re‐event rate at follow‐up
Authors: Muñoz‐García Natàlia , Cordero Alberto , Padro Teresa , Mendieta Guiomar , Vilahur Gemma , Flores Emilio , Badimon Lina 
Published: August 2024

AbstractBackgroundDyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first‐time presentation of chest pain and on‐target LDL‐C levels and intermediate FRS/ESC‐Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re‐event rate up to 6 years follow‐up.MethodsBlind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil‐to‐Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission.ResultscTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL‐6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(−) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL‐6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re‐event rate at follow‐up.ConclusionsInflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re‐event rate over a follow‐up period of up to 6 years.