Carbohydrate-Functionalized Anthracene Carboximides as Multivalent Ligands and Bio-Imaging Agents.

Anthracene carboximides (ACIs) conjugated with gluco-, galacto- and mannopyranosides are synthesized, by glycosylation of N-hydroxyethylanthracene carboximide acceptor with glycosyl donors.  Glycoconjugation of anthracene carboximide increases the aq. solubility by more than 3-fold.  The glycoconjugates display red-shifted absorption and emission, as compared to anthracene.   Large Stokes shift (λabs/ λem = 445/525 nm) and high fluorescence quantum yields (Ф) of 0.86 and 0.5 occur in THF and water, respectively. The ACI-glycosides undergo facile photodimerization in aqueous solutions, leading to the formation of the head-to-tail dimer, as a mixture of syn and anti-isomers.  Solution phase and solid-state characterizations by dynamic light scattering (DLS), microscopic imaging by atomic force (AFM) and transmission electron (TEM) microscopies reveal self-assembled vesicle structures of ACI glycosides. These self-assembled structures act as multivalent glycoclusters for ligand-specific lectin binding, as evidenced by the binding of Man-ACI to Con A, by fluorescence and turbidity assays. The conjugates do not show cellular cytotoxicity (IC50) till concentrations of 50 µM with HeLa and HepG2 cell lines and are cell-permeable, showing strong fluorescence inside the cells.  These properties enable the glycoconjugates to be used in cell imaging. The non-selective cellular uptake of the glycoconjugates suggests a passive diffusion through the membrane.

Influence of chitosan and hydroxyethyl cellulose modifications towards the design of cross-linked double networks hydrogel for diabetic wound healing.

The wound dressings' lack of antioxidant and antibacterial properties, and delayed wound healing limit their use in wound treatment and management. Recent advances in dressing materials are aimed at improving the limitations discussed above. Therefore, the aim of this study includes the preparation and characterization of oxidized hydroxyethyl cellulose (OHEC) and ferulic acid-grafted chitosan (CS-FA) hydrogel loaded with green synthesized selenium nanoparticles (Se NPs) (OHEC-CS-FA-Se NPs named as nanohydrogel) for diabetic wound healing. The structure and properties of the hydrogel was characterized by FTIR, FE-SEM, HR-TEM, EDAX, UV-Vis spectrophotometry, XRD, DLS, zeta potential and rheological studies. The findings of these experiments demonstrate that nanohydrogel possesses a variety of outstanding qualities, including an optimal gel time, good swelling characteristics, a fair water retention rate, a good degradation rate, and strong mechanical stability. Nanohydrogel has been shown to have a synergistic impact by significantly increasing antioxidant activity by scavenging ABTS and DPPH radicals. The nanohydrogel's strong biocompatibility was confirmed by cytocompatibility testing using L929 mouse fibroblast cells. In addition, the wound healing potential of nanohydrogel was tested on L929 cells by an in vitro scratch assay and the nanohydrogel showed a wound closure rate of 100 % after 12 h. In addition to this study, nanohydrogel has demonstrated significant antimicrobial properties against human and wound infection causing pathogens such as Bacillus subtilis, methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. In the animal model, almost complete diabetic wound healing was achieved on day 14 after application of the nanohydrogel. The results obtained indicate that the multifunctional bioactive nature of OHEC-CS-FA-Se NPs showed exceptional antioxidant and antibacterial potential for the treatment of infected and chronic wounds.

The lateral habenula integrates age and experience to promote social transitions in developing rats.

Social behavior deficits are an early-emerging marker of psychopathology and are linked with early caregiving quality. However, the infant neural substrates linking early care to social development are poorly understood. Here, we focused on the infant lateral habenula (LHb), a highly-conserved brain region at the nexus between forebrain and monoaminergic circuits. Despite its consistent links to adult psychopathology, this brain region has been understudied in development when the brain is most vulnerable to environmental impacts. In a task combining social and threat cues, suppressing LHb principal neurons had opposing effects in infants versus juveniles, suggesting the LHb promotes a developmental switch in social approach behavior under threat. We observed that early caregiving adversity (ECA) disrupts typical growth curves of LHb baseline structure and function, including volume, firing patterns, neuromodulatory receptor expression, and functional connectivity with cortical regions. Further, we observed that suppressing cortical projections to the LHb rescued social approach deficits following ECA, identifying this microcircuit as a substrate for disrupted social behavior. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.

The efficacy and safety of 25 µg or 50 µg oral misoprostol versus 25 µg vaginal misoprostol given at 4- or 6-hourly intervals for induction of labour in women at or beyond term with live singleton pregnancies: A systematic review and meta-analysis.

BACKGROUND: Misoprostol is widely used for cervical ripening and labour induction as it is heat-stable and inexpensive. Oral misoprostol 25 µg given 2-hourly is recommended over vaginal misoprostol 25 µg given 6-hourly, but the need for 2-hourly fetal monitoring makes oral misoprostol impractical for routine use in high-volume obstetric units in resource-constrained settings. OBJECTIVES: To compare the efficacy and safety of oral misoprostol initiated at 25 or 50 µg versus 25 µg vaginal misoprostol given at 4- to 6-hourly intervals for labor induction in women at or beyond term (≥ 37 weeks) with a single viable fetus and an unscarred uterus. SEARCH STRATEGY: We identified eligible randomized, parallel-group, labor-induction trials from recent systematic reviews. We additionally searched PubMed, Cochrane CENTRAL, Epistemonikos, and clinical trials registries from February 1, 2020 to December 31, 2022 without language restrictions. Database-specific keywords for cervical priming, labor induction, and misoprostol were used. SELECTION CRITERIA: We excluded labor-induction trials exclusively in women with ruptured membranes, in the third trimester, and those that initiated misoprostol at doses not specified in the review's objectives. The primary outcomes were vaginal birth within 24 h, cesarean section, perinatal mortality, neonatal morbidity, and maternal morbidity. The secondary outcomes were uterine hyperstimulation with fetal heart rate changes, and oxytocin augmentation. DATA COLLECTION AND ANALYSIS: Two or more authors selected studies independently, assessed risk of bias, and extracted data. We derived pooled weighted risk ratios with 95% confidence intervals (CIs) for each outcome, subgrouping trials by the dose and frequency of misoprostol regimens. We used the I2 statistic to quantify heterogeneity and the random-effects model for meta-analysis when appropriate. We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to assess certainty (confidence) in the effect estimates. MAIN RESULTS: Thirteen trials, from Canada, India, Iran, and the US, randomizing 2941 women at ≥37 weeks of gestation with an unfavorable cervix (Bishop score <6), met the eligibility criteria. Five misoprostol regimens were compared: 25 µg oral versus 25 µg vaginal, 4-hourly (three trials); 50 µg oral versus 25 µg vaginal, 4-hourly (five trials); 50 µg followed by 100 µg oral versus 25 µg vaginal, 4-hourly (two trials); 50 µg oral, 4-hourly versus 25 µg vaginal, 6-hourly (one trial); and 50 µg oral versus 25 µg vaginal, 6-hourly (two trials). The overall certainty in the evidence ranged from moderate to very low, due to high risk of bias in 11/13 trials (affecting all outcomes), unexplained heterogeneity (1/7 outcomes), indirectness (1/7 outcomes), and imprecision (4/7 outcomes). Vaginal misoprostol probably increased vaginal deliveries within 24 h compared with oral misoprostol (risk ratio [RR] 0.82, 95% CI 0.70-0.96; 11 trials, 2721 mothers; moderate-certainty evidence); this was more likely with 4-hourly than with 6-hourly vaginal regimens. The risk of cesarean sections did not appreciably differ (RR 1.00, 95% CI 0.80-1.26; 13 trials, 2941 mothers; very low-certainty evidence), although oral misoprostol 25 µg 4-hourly probably increased this risk compared with 25 µg vaginal misoprostol 4-hourly (RR 1.69, 95% CI 1.21-2.36; three trials, 515 mothers). The risk of perinatal mortality (RR 0.67, 95% CI 0.11-3.90; one trial, 196 participants; very low-certainty evidence), neonatal morbidity (RR 0.84, 95% CI 0.67-1.06; 13 trials, 2941 mothers; low-certainty evidence), and maternal morbidity (RR 0.83, 95% CI 0.48-1.44; 6 trials; 1945 mothers; moderate-certainty evidence) did not differ appreciably. The risk of uterine hyperstimulation with fetal heart rate changes may be lower with oral misoprostol (RR 0.70, 95% CI 0.52-0.95; 10 trials, 2565 mothers; low-certainty evidence). Oxytocin augmentation was probably more frequent with oral compared with vaginal misoprostol (RR 1.29, 95% CI 1.10-1.51; 13 trials, 2941 mothers; moderate-certainty evidence). CONCLUSIONS: Low-dose, 4- to 6-hourly vaginal misoprostol regimens probably result in more vaginal births within 24 h and less frequent oxytocin use compared with low-dose, 4- to 6-hourly, oral misoprostol regimens. Vaginal misoprostol may increase the risk of uterine hyperstimulation with fetal heart changes compared with oral misoprostol, without increasing the risk of perinatal mortality, neonatal morbidity, or maternal morbidity. Indirect evidence indicates that 25 µg vaginal misoprostol 4-hourly may be more effective and as safe as the recommended 6-hourly vaginal regimen. This evidence could inform clinical decisions in high-volume obstetric units in resource-constrained settings.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg-1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) ß-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.

Reducing Falls Among Community-Dwelling Older Adults From Clinicians' Perspectives: A Systems Modeling Approach.

Background and Objectives: Falls among older adults are a significant health problem globally. Studies of multicomponent fall prevention programs in randomized controlled trials demonstrate effectiveness in reducing falls; however, the translation of research into the community remains challenging. Although there is an increasing interest to understand the factors contributing to implementation barriers, the dynamic relationships between factors are less well examined. Furthermore, evidence on implementation barriers from Asia is lacking as most of these studies originate from the West. As such, this study aims to engage stakeholders in uncovering the factors that facilitate or inhibit implementing community-based fall prevention programs in Singapore, with a focus on the interrelationship between those factors. Research Design and Methods: Health care professionals familiar with fall prevention programs were invited to discuss the enablers and challenges to the implementation. This effort was facilitated using a systems modeling methodology of Group Model Building (GMB) to share ideas and create a common conceptual model of the challenges. The GMB employs various engagement techniques to draw on the experiences and perceptions of all stakeholders involved. Results: This process led to the development of a Causal Loop Diagram (CLD), a qualitative conceptual model of the dynamic relationships between the barriers and facilitators of implementing fall prevention programs. Results from the CLD show that implementation is influenced by two main drivers: health care provider factors that influenced referrals, and patient factors that influenced referral acceptance and long-term adherence. Key leverage points for potential interventions were identified as well. Discussion and Implications: The overall recommendation emphasized closer coordination and collaboration across providers to ensure sustainable and effective community-based fall prevention programs. This has to be supported by a national effort, involving a multidisciplinary stakeholder advisory group. These findings generated would be promising to guide future approaches to fall prevention.

Linker length-dependent morphologies in self-assembled structures of anthracene glucosides.

Anthracenemethyl glucosides, that possess ethylene glycol linkers connecting the glucoside with anthracene moiety, are studied herein. Koenigs-Knorr glycosylation of ethylene glycol-tethered anthracene with acetobromo glucose, followed by removal of the protecting groups, lead to the facile formation of the target glucosides. Aq. solutions of these anthracene glucosides readily undergo self-assembly, with critical aggregation concentration varying between 0.4 and 1 mM, depending on the linker, being ethylene-, di- and tetraethylene glycol, as assessed by photophysical evaluations. Circular dichroism spectra show chiral self-assembled structures for these glucosides in solution, from which a left-handed chirality is adjudged. Morphologies of the self-assembled structures of these glucosides are controlled by the linker length. With the ethylene glycol linker, vesicles form initially, around which tendrils start to grow as the concentration of the glucoside is increased. Whereas, di- and tetraethylene glycol-spaced glucosides prefer agglomerated fractal-like structures, as assessed by microscopies. The aggregation phenomenon in the latter glucosides appears to be under the non-equilibrium-driven, dissipative control.

BDNF/TrkB Is a Crucial Regulator in the Inflammation-Mediated Odontoblastic Differentiation of Dental Pulp Stem Cells.

The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there is a link between inflammation and dental tissue regeneration, identified via enhanced DPSC-mediated dentinogenesis in vitro. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor-related gene family molecule which functions through tropomyosin receptor kinase B (TrkB). While the roles of BDNF in neural tissue repair and other regeneration processes are well identified, its role in dentinogenesis has not been explored. Furthermore, the role of BDNF receptor-TrkB in inflammation-induced dentinogenesis remains unknown. The role of BDNF/TrkB was examined during a 17-day odontogenic differentiation of DPSCs. Human DPSCs were subjected to odontogenic differentiation in dentinogenic media treated with inflammation inducers (LTA or TNFα), BDNF, and a TrkB agonist (LM22A-4) and/or antagonist (CTX-B). Our data show that BDNF and TrkB receptors affect the early and late stages of the odontogenic differentiation of DPSCs. Immunofluorescent data confirmed the expression of BDNF and TrkB in DPSCs. Our ELISA and qPCR data demonstrate that TrkB agonist treatment increased the expression of dentin matrix protein-1 (DMP-1) during early DPSC odontoblastic differentiation. Coherently, the expression levels of runt-related transcription factor 2 (RUNX-2) and osteocalcin (OCN) were increased. TNFα, which is responsible for a diverse range of inflammation signaling, increased the levels of expression of dentin sialophosphoprotein (DSPP) and DMP1. Furthermore, BDNF significantly potentiated its effect. The application of CTX-B reversed this effect, suggesting TrkB`s critical role in TNFα-mediated dentinogenesis. Our studies provide novel findings on the role of BDNF-TrkB in the inflammation-induced odontoblastic differentiation of DPSCs. This finding will address a novel regulatory pathway and a therapeutic approach in dentin tissue engineering using DPSCs.

LPS-induced inflammation potentiates dental pulp stem cell odontogenic differentiation through C5aR and p38.

AIM: Inflammation is a complex host response to harmful infection or injury, and it seems to play a crucial role in tissue regeneration both positively and negatively. We have previously demonstrated that the activation of the complement C5a pathway affects dentin-pulp regeneration. However, limited information is available to understand the role of the complement C5a system related to inflammation-mediated dentinogenesis. The aim of this study was to determine the role of complement C5a receptor (C5aR) in regulating lipopolysaccharide (LPS)-induced odontogenic differentiation of dental pulp stem cells (DPSCs). MATERIAL AND METHODS: Human DPSCs were subjected to LPS-stimulated odontogenic differentiation in dentinogenic media treated with the C5aR agonist and antagonist. A putative downstream pathway of the C5aR was examined using a p38 mitogen-activated protein kinase (p38) inhibitor (SB203580). RESULTS: Our data demonstrated that inflammation induced by the LPS treatment potentiated DPSC odontogenic differentiation and that this is C5aR dependent. C5aR signaling controlled the LPS-stimulated dentinogenesis by regulating the expression of odontogenic lineage markers like dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP-1). Moreover, the LPS treatment increased the total p38, and the active form of p38 expression, and treatment with SB203580 abolished the LPS-induced DSPP and DMP-1 increase. CONCLUSIONS: These data suggest a significant role of C5aR and its putative downstream molecule p38 in the LPS-induced odontogenic DPSCs differentiation. This study highlights the regulatory pathway of complement C5aR/p38 and a possible therapeutic approach for improving the efficiency of dentin regeneration during inflammation.

Anthracenemethyl Glycosides as Supramolecular Synthons for Chiral Self-Assembly and as Probes in Cell Imaging.

Chiral self-assembly of molecules warrants optimal structural features of synthons that promote formation of such self-assembled structures. A polyaromatic moiety coupled with hydrophilic, chiral-rich carbohydrates leads to segmentation of the regions and the self-assembly to supramolecular structures. Thermodynamic stability is augmented further through chiral self-assembly of the molecules, and formation of the desired chiral supramolecular structures is achieved. In the present study, we develop anthracene glycosides as efficient synthons that, in aqueous solutions, undergo facile self-assembly and lead to chiral supramolecular structures. Anthracenemethyl O-glycosides, installed with mono- and disaccharides, are studied for their self-assembly properties. Emerging chiral structures follow the configuration of the attached sugar moiety. Monosaccharide d- and l-glycopyranoside-containing derivatives alternate between left- and right-handed chiral structures, respectively. Disaccharide-containing derivatives do not exhibit chirality, even when self-assembly occurred. Photochemical [4π + 4π] cycloaddition occurs in the self-assembled structure in aqueous solution. Cell viability assay using HeLa cells shows above 80% viable cells at a concentration of 50 µM. Bioimaging assays reveal a significant imaging of HeLa cells for anthracenemethyl d-glucopyranoside; bright imaging was observed at the perinuclear region of the cells, suggestive of an active transport of the molecules through the cell membrane. d-Galactopyranoside and l-glucopyranoside-containing derivatives show weak imaging potencies.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-Linked Hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and poor mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases bone mass, strength and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (non-phosphorylated) ß-catenin stained alveolar osteocytes. Scl-Ab had no effect on mineralized tissues of the tooth - dentin, enamel, acellular and cellular cementum. There was a non-significant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fibral structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in the Hyp mouse model of XLH.

Insights into the Structure and Function of TRIP-1, a Newly Identified Member in Calcified Tissues.

Eukaryotic initiation factor subunit I (EIF3i), also called as p36 or TRIP-1, is a component of the translation initiation complex and acts as a modulator of TGF-ß signaling. We demonstrated earlier that this intracellular protein is not only exported to the extracellular matrix via exosomes but also binds calcium phosphate and promotes hydroxyapatite nucleation. To assess other functional roles of TRIP-1, we first examined their phylogeny and showed that it is highly conserved in eukaryotes. Comparing human EIF3i sequence with that of 63 other eukaryotic species showed that more than 50% of its sequence is conserved, suggesting the preservation of its important functional role (translation initiation) during evolution. TRIP-1 contains WD40 domains and predicting its function based on this structural motif is difficult as it is present in a vast array of proteins with a wide variety of functions. Therefore, bioinformatics analysis was performed to identify putative regulatory functions for TRIP-1 by examining the structural domains and post-translational modifications and establishing an interactive network using known interacting partners such as type I collagen. Insight into the function of TRIP-1 was also determined by examining structurally similar proteins such as Wdr5 and GPSß, which contain a ß-propeller structure which has been implicated in the calcification process. Further, proteomic analysis of matrix vesicles isolated from TRIP-1-overexpressing preosteoblastic MC3T3-E1 cells demonstrated the expression of several key biomineralization-related proteins, thereby confirming its role in the calcification process. Finally, we demonstrated that the proteomic signature in TRIP1-OE MVs facilitated osteogenic differentiation of stem cells. Overall, we demonstrated by bioinformatics that TRIP-1 has a unique structure and proteomic analysis suggested that the unique osteogenic cargo within the matrix vesicles facilitates matrix mineralization.

Wnt pathway inhibitors are upregulated in XLH dental pulp cells in response to odontogenic differentiation.

X-linked hypophosphatemia (XLH) represents the most common form of familial hypophosphatemia. Although significant advances have been made in the treatment of bone pathology, patients undergoing therapy continue to experience significantly decreased oral health-related quality of life. The following study addresses this persistent oral disease by further investigating the effect of DMP1 expression on the differentiation of XLH dental pulp cells. Dental pulp cells were isolated from the third molars of XLH and healthy controls and stable transduction of full-length human DMP1 were achieved. RNA sequencing was performed to evaluate the genetic changes following the induction of odontogenic differentiation. RNAseq data shows the upregulation of inhibitors of the canonical Wnt pathway in XLH cells, while constitutive expression of full-length DMP1 in XLH cells reversed this effect during odontogenic differentiation. These results imply that inhibition of the canonical Wnt pathway may contribute to the pathophysiology of XLH and suggest a new therapeutic strategy for the management of oral disease.

Study protocol: 'a large cohort study of postnatal events in a not-for-profit referral centre in Vellore, South India'.

INTRODUCTION: In a large developing country, with diverse population characteristics and differential access to healthcare, it is important to identify factors that influence postnatal health. This knowledge will help frame recommendations to enhance universal postnatal care. METHODS AND ANALYSIS: A prospective cohort study will be conducted by recruiting all participants who deliver in a referral centre in South India during a 1-year period after written consent is obtained from them. In addition to clinical information pertaining to their delivery and demographics, details of physical health, mental health socioeconomic status and emotional support will also be collected. Every participant will be followed up physically and/or by telephonic consultation at 3, 9 and 18 months of their postnatal period to reassess their status and that of their babies. As there are several independent and dependent variables requiring multivariate analysis, a sample size of 10 000 is considered adequate. Any unplanned visits to a health facility will be enquired into and documented for analysis.During data analysis, the effect of Caesarean section, high-risk characteristics and gestational age of the baby at delivery on various outcome measures and postnatal status will be evaluated. Interpretation of the large volume of collected data will help frame recommendations to improve postnatal care ETHICS AND DISSEMINATION: The study is approved by the Institutional Review Boards (Research and Ethics Committees) of Christian Medical College, Vellore, Tamil Nadu, India (IRB 12178 date 24 June 2020).Women are provided with a detailed information sheet and written consent is obtained. They are reassured that their care will not be compromised if they do not consent to the study. Data will be available on the clinical trial portal to assist in the dissemination of results after the project is published. TRIAL REGISTRATION NUMBER: CTRI/2022/03/041343.

Evaluation of transabdominal and transperineal ultrasound-derived prostate specific antigen (PSA) density and clinical utility compared to MRI prostate volumes: A feasibility study.

PURPOSE: To investigate the accuracy of surface-based ultrasound-derived PSA-density (US-PSAD) versus gold-standard MRI-PSAD as a risk-stratification tool. METHODS: Single-centre prospective study of patients undergoing MRI for suspected prostate cancer (PCa). Four combinations of US-volumes were calculated using transperineal (TP) and transabdominal (TA) views, with triplanar measurements to calculate volume and US-PSAD. Intra-class correlation coefficient (ICC) was used to compare US and MRI volumes. Categorical comparison of MRI-PSAD and US-PSAD was performed at PSAD cut-offs <0.15, 0.15-0.20, and >0.20 ng/mL2 to assess agreement with MRI-PSAD risk-stratification decisions. RESULTS: 64 men were investigated, mean age 69 years and PSA 7.0 ng/mL. 36/64 had biopsy-confirmed prostate cancer (18 Gleason 3+3, 18 Gleason ≥3+4). Mean MRI-derived gland volume was 60 mL, compared to 56 mL for TA-US, and 65 mL TP-US. ICC demonstrated good agreement for all US volumes with MRI, with highest agreement for transabdominal US, followed by combined TA/TP volumes. Risk-stratification decisions to biopsy showed concordant agreement between triplanar MRI-PSAD and ultrasound-PSAD in 86-91% and 92-95% at PSAD thresholds of >0.15 ng/mL2 and >0.12 ng/mL2, respectively. Decision to biopsy at threshold >0.12 ng/mL2, demonstrated sensitivity ranges of 81-100%, specificity 85-100%, PPV 86-100% and NPV 83-100%. Transabdominal US provided optimal sensitivity of 100% for this clinical decision, with specificity 85%, and transperineal US provided optimal specificity of 100%, with sensitivity 87%. CONCLUSION: Transperineal-US and combined TA-TP US-derived PSA density values compare well with standard MRI-derived values and could be used to provide accurate PSAD at presentation and inform the need for further investigations.

Wound Healing Insights from Flies and Fish.

All organisms from single-cell amoebae through to Homo sapiens have evolved strategies for repairing wounds as an essential homeostatic mechanism for rebuilding their outer barrier layers after damage. In multicellular animals, this outer barrier layer is the skin, and, for more than a century, scientists have been attempting to unravel the mechanisms underpinning skin repair because of its clear clinical relevance to pathologies that range from chronic nonhealing wounds, through to excessive scarring. Most of these studies have been in rabbits and rodents, or in in vitro scratch wound models, but in the last decades, two newcomer model organisms to wound healing studies-flies and fish-have brought genetic tractability and unparalleled opportunities for live imaging to the field. These two models are complementary to one another, and to mouse and in vitro approaches, and thus offer different insights into various aspects of the wound repair process.