bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of ductus venosus Doppler and cerebroplacental ratio for the prediction of adverse perinatal outcome in high‐risk pregnancies before and after 34 weeks
Authors: Morales‐Roselló José , Bhate Rohan , Eltaweel Nashwa , Khalil Asma 
Published: May 2023

AbstractIntroductionThe objective of the study was to compare the accuracy of the ductus venosus pulsatility index (DV PI) with that of the cerebroplacental ratio (CPR) for the prediction of adverse perinatal outcome at two gestational ages: <34 and ≥34 weeks' gestation.Material and methodsThis was a retrospective study of 169 high‐risk pregnancies (72 < 34 and 97 ≥ 34 weeks) that underwent an ultrasound examination of CPR, DV Doppler and estimated fetal weight at 22–40 weeks. The CPR and DV PI were converted into multiples of the median, and the estimated fetal weight into centiles according to local references. Adverse perinatal outcome was defined as a composite of abnormal cardiotocogram, intrapartum pH requiring cesarean delivery, 5′ Apgar score <7, neonatal pH <7.10 and admission to neonatal intensive care unit. Values were plotted according to the interval to labor to evaluate progression of abnormal Doppler values, and their accuracy was evaluated at both gestational periods, alone and combined with clinical data, by means of univariable and multivariable models, using the Akaike information criteria (AIC) and the area under the curve (AUC).ResultsPrior to 34 weeks' gestation, DV PI was the latest parameter to become abnormal. However, it was a poor predictor of adverse perinatal outcome (AUC 0.56, 95% CI: 0.40–0.71, AIC 76.2, p > 0.05), and did not improve the predictive accuracy of CPR for adverse perinatal outcome (AUC 0.88, 95% CI: 0.79–0.97, AIC 52.9, p < 0.0001). After 34 weeks' gestation, the chronology of the DV PI and CPR anomalies overlapped, but again DV PI was a poor predictor for adverse perinatal outcome (AUC 0.62, 95% CI: 0.49–0.74, AIC 120.6, p > 0.05), that did not improve the CPR ability to predict adverse perinatal outcome (AUC 0.80, 95% CI: 0.67–0.92, AIC 106.8, p < 0.0001). The predictive accuracy of CPR prior to 34 weeks persisted when the gestational age at delivery was included in the model (AUC 0.91, 95% CI: 0.81–1.00, AIC 46.3, p < 0.0001, vs AUC 0.86, 95% CI: 0.72–1, AIC 56.1, p < 0.0001), and therefore was not determined by prematurity.ConclusionsCPR predicts adverse perinatal outcome better than DV PI, regardless of gestational age. Larger prospective studies are needed to delineate the role of ultrasound tools of fetal wellbeing assessment in predicting and preventing adverse perinatal outcome.
Pathophysiological mechanisms of reduced physical activity: Insights from the human step reduction model and animal analogues
Authors: Sarto Fabio , Bottinelli Roberto , Franchi Martino V. , Porcelli Simone , Simunič Bostjan , Pišot Rado , Narici Marco V. 
Published: May 2023

AbstractPhysical inactivity represents a heavy burden for modern societies and is spreading worldwide, it is a recognised pandemic and is the fourth cause of global mortality. Not surprisingly, there is an increasing interest in longitudinal studies on the impact of reduced physical activity on different physiological systems. This narrative review focuses on the pathophysiological mechanisms of step reduction (SR), an experimental paradigm that involves a sudden decrease in participants' habitual daily steps to a lower level, mimicking the effects of a sedentary lifestyle. Analogous animal models of reduced physical activity, namely, the “wheel‐lock” and the “cage reduction” models, which can provide the foundation for human studies, are also discussed. The empirical evidence obtained thus far shows that even brief periods of reduced physical activity can lead to substantial alterations in skeletal muscle health and metabolic function. In particular, decrements in lean/muscle mass, muscle function, muscle protein synthesis, cardiorespiratory fitness, endothelial function and insulin sensitivity, together with an increased fat mass and inflammation, have been observed. Exercise interventions seem particularly effective for counteracting these pathophysiological alterations induced by periods of reduced physical activity. A direct comparison of SR with other human models of unloading, such as bed rest and lower limb suspension/immobilisation, is presented. In addition, we propose a conceptual framework aiming to unravel the mechanisms of muscle atrophy and insulin resistance in the specific context of reduced ambulatory activity. Finally, methodological considerations, knowledge gaps and future directions for both animal and human models are also discussed in the review.
Preclinical safety and biodistribution assessment of Ad‐KCNH2‐G628S administered via atrial painting in New Zealand white rabbits
Authors: Benson Janet M. , Wang Gensheng , Hutt Julie A. , Wu Guodong , Kaminsky Stephen M. , Cram Sara , Barur Rajeshkumar , Donahue J. Kevin 
Published: May 2023

AbstractPost‐operative atrial fibrillation (POAF) is the most common complication after cardiac surgery. Despite implementation of several pharmacological strategies, incidence of POAF remains at approximately 30%. An adenovirus vector encoding KCNH2‐G628S has proven efficacious in a porcine model of AF. In this preclinical study, 1.5 × 1010 or 1.5 × 1012 Ad‐KCNH2‐G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 1012 vp were applied to the whole epicardial surface of New Zealand White rabbits. Saline and vector vehicle served as procedure controls. Animals were followed for up to 42 days. Vector genomes persisted in the atria up to 42 days, with no distribution to extra‐thoracic organs. There were no adverse effects attributable to test article on standard toxicological endpoints or on blood pressure, left atrial or ventricular ejection fractions, electrocardiographic parameters, or serum IL‐6 or troponin concentrations. Mononuclear infiltration of the myocardium of the atrial free walls of low‐dose, but not high‐dose animals was observed at 7 and 21 days, but these changes did not persist or affect cardiac function. After scaling for heart size, results indicate the test article is safe at doses up to 25 times the maximum proposed for the human clinical trial.
Deprescribing in a multimorbid older adult: A case vignette study among community pharmacists and primary care physicians
Authors: Bužančić Iva , Ortner Hadžiabdić Maja 
Published: May 2023

AbstractCollaborative deprescribing can include pharmacists' medication review with identification and suggestion of potential deprescribing targets to physicians. Case vignettes can be a valuable method for researching variations in clinical decision making, especially in settings unaccustomed to newer clinical approaches such as deprescribing. This study aimed to explore if pharmacists can identify deprescribing targets and if physicians would accept pharmacist's deprescribing rationales. A cross‐sectional study was performed using an online case vignette based on a real‐life elderly patient. Pharmacists were asked to indicate which medicines they would recommend deprescribing, alongside a rationale. Physicians were asked to state their acceptance of the proposed pharmacist's deprescribing suggestion. Pharmacists gave 1275 deprescribing rationales, and most were given for deprescribing opioids, NSAID and diuretics. Physicians would accept rationales to deprescribe a median of 10 medicines, while pharmacist would recommend deprescribing a median of six medicines. Most difference lays in deprescribing of preventative medicines. Healthcare providers share agreement on deprescribing targets, but pharmacists show hesitancies in making recommendations that could hamper potential collaboration. Action is needed to improve pharmacists' skills in recognizing deprescribing targets and confidence in making suggestions, which could lead to opening of possibilities for joint patient care.
The therapeutic alliance in context: Institutional factors that impact social work with families
Authors: de‐Toro Consuagra Ximena , Sharim Kovalskys Dariela , Puig‐Cruells Carmina , Muñoz‐Guzmán Carolina 
Published: May 2023

AbstractThe therapeutic alliance is among the factors associated with positive results in therapy and has been extensively studied in psychotherapy. However, it has received less attention in social work and family intervention. Considering that such intervention occurs mainly within the framework of institutions and public policies, this article aims to identify the contextual factors that facilitate or hinder the therapeutic alliance between family members and social workers within the child protection system, taking the Chilean protection system as a case study. This longitudinal study followed six professional–caregiver dyads for 11 months using various qualitative techniques. The facilitating factors included the strengths approach of the child protection agency, family participation, a friendly work environment, and external supervision from a senior social worker. Among the obstacles were the high numbers of cases per professional, the undervaluing of their work, excessive workloads, stigma towards the system, and the mandatory nature of services. Facilitating factors were linked to the initiatives of the protection agency, while limitations were related to the type of welfare system. Similar obstacles and facilitators were found at the international level regardless of the kind of child protection system. The study concludes with recommendations for decision‐makers and social worker educators.
Characterization of novel CACNA1A splice variants by RNA‐sequencing in patients with episodic or congenital ataxia
Authors: Riant Florence , Burglen Lydie , Corpechot Michaelle , Robert Julien , Durr Alexandra , Solé Guilhem , Petit Florence , Freihuber Cécile , De Marco Olivier , Sarret Catherine , Castelnovo Giovanni , Devillard Françoise , Afenjar Alexandra , Héron Bénédicte , Lasserve Elisabeth Tournier 
Published: May 2023

AbstractLoss of function variants in CACNA1A cause a broad spectrum of neurological disorders, including episodic ataxia, congenital or progressive ataxias, epileptic manifestations or developmental delay. Variants located on the AG/GT consensus splice sites are usually considered as responsible of splicing defects, but exonic or intronic variants located outside of the consensus splice site can also lead to abnormal splicing. We investigated the putative consequences on splicing of 11 CACNA1A variants of unknown significance (VUS) identified in patients with episodic ataxia or congenital ataxia. In silico splice predictions were performed and RNA obtained from fibroblasts was analyzed by Sanger sequencing. The presence of abnormal transcripts was confirmed in 10/11 patients, nine of them were considered as deleterious and one remained of unknown significance. Targeted next‐generation RNA sequencing was done in a second step to compare the two methods. This method was successful to obtain the full cDNA sequence of CACNA1A. Despite the presence of several isoforms in the fibroblastic cells, it detected most of the abnormally spliced transcripts. In conclusion, RNA sequencing was efficient to confirm the pathogenicity of nine novel CACNA1A variants. Sanger or Next generation methods can be used depending on the facilities and organization of the laboratories.
Adults with lower‐limb amputation: Reduced multifidi muscle activity and extensor muscle endurance is associated with worse physical performance
Authors: Sions Jaclyn M. , Seth Mayank , Beisheim‐Ryan Emma H. , Hicks Gregory E. , Pohlig Ryan T. , Horne John R. 
Published: May 2023

AbstractTrunk muscles may be an overlooked region of deficits following lower‐limb amputation (LLA). This study sought to determine the extent that trunk muscle deficits are associated with physical function following amputation. Sedentary adults with a unilateral transtibial‐ (n = 25) or transfemoral‐level (n = 14) amputation were recruited for this cross‐sectional research study. Participants underwent a clinical examination that included ultrasound imaging of the lumbar multifidi muscles, the modified Biering‐Sorensen Endurance Test (mBSET), and performance‐based measures, that is, the Timed Up and Go (TUG), Berg Balance Scale (BBS), and 10‐m Walk Test (10mWT). Associations between trunk muscle metrics and performance were explored with regression modeling, while considering covariates known to impact performance postamputation (p ≤ 0.100). Average ultrasound‐obtained, lumbar multifidi activity was 14% and 16% for transfemoral‐ and transtibial‐level amputations, respectively, while extensor endurance was 37.34 and 12.61 s, respectively. For TUG, nonamputated‐side multifidi activity and an interaction term (level x non‐amputated‐side multifidi activity) explained 9.4% and 6.2% of the total variance, respectively. For 10mWT, beyond covariates, non‐amputated‐side multifidi activity and the interaction term explained 6.1% and 5.8% of the total variance, respectively. For TUG, extensor endurance and an interaction term (level x mBSET) explained 11.9% and 8.3% of the total variance beyond covariates; for BBS and 10mWT, extensor endurance explained 11.2% and 17.2% of the total variance, respectively. Findings highlight deficits in lumbar multifidi activity and extensor muscle endurance among sedentary adults with a LLA; reduced muscle activity and endurance may be important factors to target during rehabilitation to enhance mobility‐related outcomes.
Adult progenitor rejuvenation with embryonic factors
Authors: Wang Peng , Liu Xupeng , Chen Yu , Jun‐Hao Elwin Tan , Yao Ziyue , Min‐Wen Jason Chua , Yan‐Jiang Benjamin Chua , Ma Shilin , Ma Wenwu , Luo Lanfang , Guo Luyao , Song Dan , Shyh‐Chang Ng 
Published: May 2023

AbstractDuring ageing, adult stem cells' regenerative properties decline, as they undergo replicative senescence and lose both their proliferative and differentiation capacities. In contrast, embryonic and foetal progenitors typically possess heightened proliferative capacities and manifest a more robust regenerative response upon injury and transplantation, despite undergoing many rounds of mitosis. How embryonic and foetal progenitors delay senescence and maintain their proliferative and differentiation capacities after numerous rounds of mitosis, remains unknown. It is also unclear if defined embryonic factors can rejuvenate adult progenitors to confer extended proliferative and differentiation capacities, without reprogramming their lineage‐specific fates or inducing oncogenic transformation. Here, we report that a minimal combination of LIN28A, TERT, and sh‐p53 (LTS), all of which are tightly regulated and play important roles during embryonic development, can delay senescence in adult muscle progenitors. LTS muscle progenitors showed an extended proliferative capacity, maintained a normal karyotype, underwent myogenesis normally, and did not manifest tumorigenesis nor aberrations in lineage differentiation, even in late passages. LTS treatment promoted self‐renewal and rescued the pro‐senescence phenotype of aged cachexia patients' muscle progenitors, and promoted their engraftment for skeletal muscle regeneration in vivo. When we examined the mechanistic basis for LIN28A's role in the LTS minimum combo, let‐7 microRNA suppression could not fully explain how LIN28A promoted muscle progenitor self‐renewal. Instead, LIN28A was promoting the translation of oxidative phosphorylation mRNAs in adult muscle progenitors to optimize mitochondrial reactive oxygen species (mtROS) and mitohormetic signalling. Optimized mtROS induced a variety of mitohormetic stress responses, including the hypoxic response for metabolic damage, the unfolded protein response for protein damage, and the p53 response for DNA damage. Perturbation of mtROS levels specifically abrogated the LIN28A‐driven hypoxic response in Hypoxia Inducible Factor‐1α (HIF1α) and glycolysis, and thus LTS progenitor self‐renewal, without affecting normal or TS progenitors. Our findings connect embryonically regulated factors to mitohormesis and progenitor rejuvenation, with implications for ageing‐related muscle degeneration.
Prediction, prevention, and treatment of post reperfusion syndrome in adult orthotopic liver transplant patients
Authors: DeMaria Samuel , Nolasco Lyle , Igwe Divya , Jules Robert St. , Bekki Yuki , Smith Natalie K. 
Published: May 2023

AbstractImportanceThis review explores proposed predictors, preventative measures, and treatment options for post‐reperfusion syndrome (PRS) in liver transplantation and provides updated data for clinicians.ObjectivesThe review aims to understand the status and progress made regarding PRS during orthotopic liver transplantation. Moreover, the predictors of PRS will be analyzed to highlight risk factors. Mediators of PRS and the modes of action of the currently available preventative and management agents that target particular PRS factors will be investigated.Data SourcesData is drawn from secondary sources from databases of peer‐reviewed journals. The bibliographies of select sources were also used to obtain additional data studies using the ‘snowball’ method.Study SelectionThe initial data search provided 1394 studies analyzed using PRISMA Extension for Scoping Reviews (PRISMA‐ScR) guidelines. After applying the eligibility criteria, 18 studies were fit for inclusion.ResultsThe study identified that in addition to the severity of underlying medical conditions, other significant PRS predictors included patient age, sex, duration of cold ischemia, and the surgical technique. While the use of epinephrine and norepinephrine is well‐established, further preventative measures commonly involve specifically targeting known mediators of the syndrome, such as antioxidants, vasodilators, free radical scavengers, and anticoagulants. Current management strategies involve supportive therapy. Machine Perfusion may ultimately decrease the risk of PRS.ConclusionPRS still holds unknowns, including the underlying pathophysiology, controllable factors, and ideal management practices. There is a need for further study, particularly prospective trials since liver transplantation is the gold standard for treating end‐stage liver disease and the incidence of PRS remains high.
Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease
Authors: van Kraaij Sebastiaan J. W. , Pereira Diana R. , Smal Bastiaan , Summo Luciana , Konkel Anne , Lossie Janine , Busjahn Andreas , Grammatopoulos Tom N. , Klaassen Erica , Fischer Robert , Schunck Wolf‐Hagen , Gal Pim , Moerland Matthijs 
Published: May 2023

AbstractThe development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue‐level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross‐sectional case–control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF‐15, IL‐6, NT‐proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide‐adenine‐dinucleotide‐hydrogen (NADH) content in skin as well as reduced passive leg movement‐induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood‐based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis.
Translatability of in vitro potency to clinical efficacious exposure: A retrospective analysis of FDA‐approved targeted small molecule oncology drugs
Authors: Kotani Naoki , Ito Kiyomi 
Published: May 2023

AbstractIn vitro potency is one of the important parameters representing efficacy potential of drugs and commonly used as benchmark of efficacious exposure at early clinical development. There are limited numbers of studies which systematically investigate on how predictive in vitro potency is to estimate therapeutic drug exposure, especially those focusing on targeted anticancer agents despite the recent increase in approvals. This study aims to fill in such knowledge gaps. A total of 87 small molecule targeted drugs approved for oncology indication between 2001 and 2020 by the US Food and Drug Administration (FDA) were identified; relevant preclinical and clinical data were extracted from the public domain. Relationships between the in vitro potency and the therapeutic dose or exposure (unbound average drug concentration [Cu,av] as the primary exposure metrics) were assessed by descriptive analyses. The Spearman's rank correlation test showed slightly better correlation of the Cu,av (ρ = 0.232, p = 0.041) rather than the daily dose (ρ = 0.186, p = 0.096) with the in vitro potency. Better correlation was observed for the drugs for hematologic malignancies compared with those for solid tumors (root mean square error: 140 [n = 28] versus 297 [n = 59]). The present study shows that in vitro potency is predictive to estimate the therapeutic drug exposure to some extent, whereas the general trend of overexposure was observed. The results suggested that in vitro potency alone is not sufficient and robust enough to estimate the clinically efficacious exposure of molecularly targeted small molecule oncology drugs. The totality of data, including both nonclinical and clinical, needs to be considered for dose optimization.
From clinical data management to clinical data science: Time for a new educational model
Authors: Ittenbach Richard F. 
Published: May 2023

AbstractThe purpose of this article is to propose and provide a blueprint for a graduate‐level curriculum in clinical data science, devoted to the measurement, acquisition, care, treatment, and inferencing of clinical research data. The curriculum presented here contains a series of five required core courses, five required research courses, and a list of potential electives. The coursework draws from but does not duplicate content from the foundational areas of biostatistics, clinical medicine, biomedical informatics, and regulatory affairs, and may be reproduced by any institution interested in and capable of offering such a program. This new curriculum in “clinical” data science will prepare students for work in academic, industry, and government research settings as well as offer a unifying knowledge base for the profession.