Comparing the resource implications of old and new colorectal adenoma surveillance guidelines in Australia.

BACKGROUND: The latest update to the Australian adenoma surveillance guideline in 2018 introduced a novel risk stratification system with updated surveillance recommendations. The resource implications of adopting this new system are unclear. AIMS: To quanitfy the resource demands of adopting new over old adenoma surveillance guidelines. METHODS: We studied data from 2443 patients undergoing colonoscopies, in which a clinically significant lesion was identified in their latest, or previous procedure(s) across five Australian hospitals. We excluded procedures with inflammatory bowel disease, new or prior history of colorectal cancer or resection, inadequate bowel preparation and incomplete procedures. Old and new Australian surveillance intervals were calculated according to the number, size and histological characteristics of lesions identified. We used these data to compare the rate of procedures according to each guideline. RESULTS: Based on the procedures for 766 patients, the new surveillance guidelines significantly increased the number of procedures allocated an interval of 1 year (relative risk (RR): 1.57, P = 0.009) and 10 years (RR: 3.83, P < 0.00001) and reduced those allocated to half a year (RR: 0.08, P = 0.00219), 3 years (RR: 0.51, P < 0.00001) and 5 years (RR: 0.59, P < 0.00001). Overall, this reduced the relative number of surveillance procedures by 21% over 10 years (25.92 vs 32.78 procedures/100 patient-years), which increased to 22% after excluding patients 75 or older at the time of surveillance (19.9 vs 25.65 procedures/100 patient-years). CONCLUSION: The adoption of the latest Australian adenoma surveillance guidelines can reduce demand for surveillance colonoscopy by more than a fifth (21-22%) over 10 years.

Re-defining 18 F-DCFPyl prostate-specific membrane antigen positron emission tomography detected local recurrence from radical prostatectomy histopathology.

OBJECTIVE: To assess topographic concordance between the histopathological features of patients' radical prostatectomy (RP) specimens and the location of the prostate-specific membrane antigen positron emission tomography (PSMA PET) local recurrences, qualitatively and quantitatively. PATIENTS AND METHODS: Our cohort was selected from the 100 men who received a 18 F-DCFPyL PET scan in the IMPPORT trial (Australian New Zealand Clinical Trials Registry Number: ACTRN12618001530213), a prospective non-randomised study completed by GenesisCare Victoria. Eligibility included patients with a rising prostate-specific antigen (PSA) level (>0.2 ng/mL) after RP and PSMA PET detected local recurrence. Histopathological parameters collated included the location of tumour, extraprostatic extension (EPE), and positive margins. Criteria for the location and 'concordance' between histopathological features and local recurrences were pre-defined. RESULTS: A total of 24 patients were eligible; the median age was 71 years, the median PSA level was 0.37 ng/mL, and the time between RP and PSMA PET was 2.6 years. In all, 15 patients had recurrences within the vesicourethral anastomotic region and nine within the lateral surgical margins. There was 100% concordance in the left-right plane between tumour location and local recurrence, with 79% of these lesions concordant three-dimensionally; across craniocaudal, left-right, and anterior-posterior planes. In all, 10 of the 16 (63%) patients with EPE and five of the nine patients with positive margins had three-dimensional concordance between their pathology and their local recurrence. In quantitative assessment, 17 of the 24 patients, had local recurrences that correlated with the location of their original tumour in the craniocaudal plane. CONCLUSION: Local recurrence is highly concordant with the position of the tumour within the prostate. Predicting the location of local recurrence using the location of the EPE and positive margins is less helpful. Further investigation into this field, could impact surgical technique and salvage radiotherapy clinical target volume.

Identifying potential immuno-oncology targets in salivary gland mucoepidermoid carcinoma based on inflammatory status and treatment response.

BACKGROUND: Mucoepidermoid carcinoma is a rare salivary gland malignant tumour. This study aimed to investigate inflammatory and immune signatures of mucoepidermoid carcinoma by identifying potential proteo-transcriptomic biomarkers towards the development of precision immuno-oncology treatment strategies. METHODS: A total of 30 biopsies obtained from patients diagnosed with mucoepidermoid carcinoma between 2013 and 2022 were analysed after H&E staining for scoring of histological inflammatory stroma subtypes and inflammatory hotspots with QuPath. Multiplex immunofluorescence staining and NanoString nCounter PanCancer IO 360™ panel were used to assess stroma and tumour inflammation signatures in high grade mucoepidermoid carcinoma cases in the tumour microenvironment via proteomics and transcriptomics, respectively. RESULTS: Inflammatory cells within the histological inflammatory stroma inflammatory (HIS-INF/hot) tumour neighbourhoods were greater compared to the histological inflammatory stroma-immune desert (HIS-ID/cold) (p = 0.001). A similar trend was observed between treatment non-responders and responders in stroma neighbourhoods (p = 0.0625) and in stroma-to-interface inflammatory hotspots (p = 0.0081), indicating an augmented inflammatory response in hot tumours and non-responders. Furthermore, there were striking differences in the expression of pan-immune leukocyte marker CD45 between responders and non responders particularly in the tumour neighbourhoods (p = 0.0341), but such were not robust for PD-1 and macrophage fractions. Additionally, transcriptomic analysis revealed key differences in leukocyte activation profiles between responders and non-responders. CONCLUSION: This preliminary report unveils the importance of assessing immune leukocyte cellular fractions and pathways for future prognostic biomarker discoveries in mucoepidermoid carcinoma as per the involvement of CD45-driven inflammatory and immune mediators in high grade mucoepidermoid carcinoma in non-responders to treatment. These findings will potentially contribute to the development of novel personalised immunotherapies.

A single-center, retrospective analysis to compare measurement of fibrinogen using the TEG6 analyzer to the Clauss measurement in children undergoing heart surgery.

BACKGROUND: Newer generation viscoelastic tests, TEG6s, offer point-of-care hemostatic therapy in adult patients. However, their efficacy in estimating fibrinogen levels in pediatric patients undergoing cardiac surgery is not well established. AIMS: This study evaluates TEG6s for estimating fibrinogen levels in pediatric cardiac surgery patients and its predictive capability for post-bypass hypofibrinogenemia. METHODS: A single-center, retrospective study on pediatric patients (under 18 years) who underwent cardiac surgery with cardiopulmonary bypass from August 2020 and November 2022. Blood samples for estimated whole blood functional fibrinogen level via TEG6s (Haemonetics Inc.) and concurrent laboratory-measured plasma fibrinogen via von Clauss assay were collected at pre- and post-cardiopulmonary bypass. RESULTS: Paired data for TEG6s estimated functional fibrinogen levels and plasma fibrinogen were analyzed for 432 pediatric patients pre-bypass. It was observed that functional fibrinogen consistently overestimated plasma fibrinogen across all age groups with a mean difference of 138 mg/dL (95% confidence interval [CI]: 128-149 mg/dL). This positive bias in the pre-bypass data was confirmed by Bland-Altman analysis. Post-bypass, functional fibrinogen estimates were comparable to plasma fibrinogen in all patient groups with a mean difference of -6 mg/dL (95% CI: -20-8 mg/dL) except for neonates, where functional fibrinogen levels underestimated plasma fibrinogen with a mean difference of -38 mg/dL (95% CI: -64 to -12 mg/dL). The predictive accuracy of functional fibrinogen for detecting post-bypass hypofibrinogenemia (plasma fibrinogen ≤250 mg/dL) demonstrated overall fair accuracy in all patients, indicated by an area under the curve of 0.73 (95% CI: 0.65-0.80) and good accuracy among infants, with an area under the curve of 0.80 (95% CI: 0.70-0.90). Similar performance was observed in predicting critical post-bypass hypofibrinogenemia (plasma fibrinogen ≤200 mg/dL). Based on these analyses, optimal cutoffs for predicting post-bypass hypofibrinogenemia were established as a functional fibrinogen level ≤270 mg/dL and MAFF ≤15 mm. CONCLUSION: This study demonstrates that whole blood functional fibrinogen, as estimated by TEG6s, tends to overestimate baseline plasma fibrinogen levels in pediatric age groups but aligns more accurately post-cardiopulmonary bypass, particularly in neonates and infants, suggesting its potential as a point-of-care tool in pediatric cardiac surgery. However, the variability in TEG6s performance before and after bypass highlights the need for careful interpretation of its results in clinical decision-making. Despite its contributions to understanding TEG6s in pediatric cardiac surgery, the study's design and inherent biases warrant cautious application of these findings in clinical settings.

Structural Characterization and Cytotoxic Activity Evaluation of Ulvan Polysaccharides Extracted from the Green Algae Ulva papenfussii.

Ulvan, a sulfated heteropolysaccharide with structural and functional properties of interest for various uses, was extracted from the green seaweed Ulva papenfussii. U. papenfussii is an unexplored Ulva species found in the South China Sea along the central coast of Vietnam. Based on dry weight, the ulvan yield was ~15% (w/w) and the ulvan had a sulfate content of 13.4 wt%. The compositional constitution encompassed L-Rhamnose (Rhap), D-Xylose (Xylp), D-Glucuronic acid (GlcAp), L-Iduronic acid (IdoAp), D-Galactose (Galp), and D-Glucose (Glcp) with a molar ratio of 1:0.19:0.35:0.52:0.05:0.11, respectively. The structure of ulvan was determined using High-Performance Liquid Chromatography (HPLC), Fourier Transform Infrared Spectroscopy (FT-IR), and Nuclear Magnetic Resonance spectroscopy (NMR) methods. The results showed that the extracted ulvan comprised a mixture of two different structural forms, namely ("A3s") with the repeating disaccharide [→4)-ß-D-GlcAp-(1→4)-α-L-Rhap 3S-(1→]n, and ("B3s") with the repeating disaccharide [→4)-α-L-IdoAp-(1→4)-α-L-Rhap 3S(1→]n. The relative abundance of A3s, and B3s was 1:1.5, respectively. The potential anticarcinogenic attributes of ulvan were evaluated against a trilogy of human cancer cell lineages. Concomitantly, Quantitative Structure-Activity Relationship (QSAR) modeling was also conducted to predict potential adverse reactions stemming from pharmacological interactions. The ulvan showed significant antitumor growth activity against hepatocellular carcinoma (IC50 ≈ 90 µg/mL), human breast cancer cells (IC50 ≈ 85 µg/mL), and cervical cancer cells (IC50 ≈ 67 µg/mL). The QSAR models demonstrated acceptable predictive power, and seven toxicity indications confirmed the safety of ulvan, warranting its candidacy for further in vivo testing and applications as a biologically active pharmaceutical source for human disease treatment.

HIV-related stigma, symptoms of depression and their association with suicidal ideation among people living with HIV in Ho Chi Minh City, Vietnam.

To date, little are known about HIV-related stigma, symptoms of depression (SOD) and suicidal ideation among people living with HIV (PLHIV) in Vietnam. This study aimed to estimate the level of stigma, SOD and suicidal ideation and to explore the direction and magnitude of the relationship between stigma, SOD and suicidal ideation among Vietnamese PLHIV. A cross-sectional study was conducted in four outpatient clinics providing healthcare services including antiretroviral therapy (ART) for PLHIV in Ho Chi Minh City. At each clinic, patients were chosen using the systematic sampling technique. Participants underwent face-to-face interviews through a pre-defined structural questionnaire that included validated scales. Among 777 PLHIV in the analysis, most were male (81.1%) and the average age was 34.3 (SD = 8.8) years. Two-thirds of PLHIV had a moderate-to-high level of HIV stigma. Symptoms of depression were identified in 41.4% of PLHIV. Suicidal ideation was reported by 26.3% of PLHIV. Based on univariate and multivariate logistic regression, higher levels of SOD and HIV stigma were positively associated with suicidal ideation. For PLHIV with extreme stigma and SOD, the probability of having suicidal ideation was up to 80%. The prevalence and association found in this study indicates that interventions for SOD and stigma not only help reduce these two problems but also help address and minimize suicidal ideation in this vulnerable population. In Vietnam, to optimize such interventions, the involvement of families and communities is crucial.

Novel biogenic gold nanoparticles stabilized on poly(styrene-co-maleic anhydride) as an effective material for reduction of nitrophenols and colorimetric detection of Pb(II).

Biogenic gold nanoparticles (AuNPs) have been extensively studied for the catalytic conversion of nitrophenols (NP) into aminophenols and the colorimetric quantification of heavy metal ions in aqueous solutions. However, the high self-agglomeration ability of colloidal nanoparticles is one of the major obstacles hindering their application. In the present study, we offered novel biogenic AuNPs synthesized by a green approach using Cistanche deserticola (CD) extract as a bioreducing agent and stabilized on poly(styrene-co-maleic anhydride) (PSMA). The prepared Au@PSMA nanoparticles were characterized by various techniques (HR-TEM, SEAD, FE-SEM, DLS, TGA, XRD, and FTIR) and studied for two applications: the catalytic reduction of 3-NP by NaBH4 and the sensing detection of Pb2+ ions. The optimal conditions for the synthesis of AuNPs were investigated and established at 60 °C, 20 min, pH of 9, and 0.5 mM Au3+. Morphological studies showed that AuNPs synthesized by CD extract were mostly spherical with a mean diameter of 25 nm, while the size of polymer-integrated AuNPs was more than two-fold larger. Since PSMA acted as a matrix keeping the nanoparticles from coagulation and maintaining the optimal surface area, AuNPs integrated with PSMA showed higher catalytic efficiency with a faster reaction rate and lower activation energy than conventional nanoparticles. Au@PSMA could completely reduce 3-NP within 10 min with a rate constant of 0.127 min-1 and activation energy of 9.96 kJ/mol. The presence of PSMA also improved the stability and recyclability of AuNPs. Used as a sensor, Au@PSMA exhibited excellent sensitivity and selectivity for Pb2+ ions with a limit of detection of 0.03 µM in the linear range of 0-100 µM. The study results suggested that Au@PSMA could be used as a promising catalyst for the reduction of NP and the colorimetric sensor for detection of Pb2+ ions in aqueous environmental samples.

Experimental and computational investigation of a green Knoevenagel condensation catalyzed by zeolitic imidazolate framework-8.

ZIF-8 is a highly porous, stable, and abundant surface area material that can be used as an environmentally friendly catalyst for Knoevenagel condensations. The effects of the ratio of the reactants (benzaldehyde (BA):ethyl cyanoacetate (ECA)), reaction temperature, and catalyst concentration were systematically investigated using a ZIF-8 catalyst and water as the solvent. ZIF-8 (3-5 wt%) showed excellent catalytic performance with an almost complete conversion of BA in less than 6 h with a BA:ECA molar ratio of 1:2 at different temperatures. At 60 °C, the BA conversion rate and product selectivity of the reaction reached their highest values after 4 h with a BA:ECA molar ratio of 1:1. When employing 5.0 wt% ZIF-8, almost complete BA conversion was achieved after 3 h at room temperature. ZIF-8 also demonstrated good recyclability with almost no change in its catalytic activity over five cycles. The proposed reaction mechanism is based on the catalytic activity of the basic N sites on the surface of ZIF-8, and is supported by density functional theory calculations. The present approach provides a promising strategy for the construction of simple and environmentally friendly ZIF-8 catalysts.

The Endo-α(1,3)-Fucoidanase Mef2 Releases Uniquely Branched Oligosaccharides from Saccharina latissima Fucoidans.

Fucoidans are complex bioactive sulfated fucosyl-polysaccharides primarily found in brown macroalgae. Endo-fucoidanases catalyze the specific hydrolysis of α-L-fucosyl linkages in fucoidans and can be utilized to tailor-make fucoidan oligosaccharides and elucidate new structural details of fucoidans. In this study, an endo-α(1,3)-fucoidanase encoding gene, Mef2, from the marine bacterium Muricauda eckloniae, was cloned, and the Mef2 protein was functionally characterized. Based on the primary sequence, Mef2 was suggested to belong to the glycosyl hydrolase family 107 (GH107) in the Carbohydrate Active enZyme database (CAZy). The Mef2 fucoidanase showed maximal activity at pH 8 and 35 °C, although it could tolerate temperatures up to 50 °C. Ca2+ was shown to increase the melting temperature from 38 to 44 °C and was furthermore required for optimal activity of Mef2. The substrate specificity of Mef2 was investigated, and Fourier transform infrared spectroscopy (FTIR) was used to determine the enzymatic activity (Units per µM enzyme: Uf/µM) of Mef2 on two structurally different fucoidans, showing an activity of 1.2 × 10-3 Uf/µM and 3.6 × 10-3 Uf/µM on fucoidans from Fucus evanescens and Saccharina latissima, respectively. Interestingly, Mef2 was identified as the first described fucoidanase active on fucoidans from S. latissima. The fucoidan oligosaccharides released by Mef2 consisted of a backbone of α(1,3)-linked fucosyl residues with unique and novel α(1,4)-linked fucosyl branches, not previously identified in fucoidans from S. latissima.

Medication-related osteonecrosis of the jaw: Osteoclast profile in comparison with osteoradionecrosis of the jaw and osteomyelitis of the jaw.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a pathology condition of jaw bone caused by a side effect of medications prescribed for skeletal disease. The mechanism of MRONJ is still unknown now. Osteoclasts are cells directly influenced by the medication and the modification in cells metabolisms by the drugs lead to MRONJ. Thus, this study aimed to investigate the osteoclasts morphology, quantity, and comparing with other necrotic diseases. METHODS: Thirty-eight (38) subjects, including cases with MRONJ (n = 11), osteoradionecrosis of the jaw (n = 9), osteomyelitis of the jaw (n = 9), and normal jaw bone (n = 9), were studied. Hematoxylin-and-eosin-stained slides of these diagnosed cases were used to evaluate osteoclasts' characteristics. Immunohistochemistry of TRAP was performed to observed the function of osteoclasts. These characteristics of osteoclasts were also evaluated in the relationship with the histological features using regression analysis. RESULTS: The results showed that osteoclasts in MRONJ enhance activity by increasing the size and the quantity (p < 0.05). The presence of osteoblasts, inflammatory cells, and bacterial colonies showed a strong correlation with the change in morphology and the number of osteoclasts (p < 0.05). However, the TRAP-positive mean number and the TRAP intensity of osteoclasts in MRONJ did not show a significant difference with those in other groups (p > 0.05). CONCLUSION: In conclusion, osteoclasts in MRONJ increase the number and become bigger with multi-nuclei which might relate to the presence of osteoblasts, inflammation, and microorganisms. This finding supports the idea osteoclasts might be the main key to investigate MRONJ.

Natural core-shell structure activated carbon beads derived from Litsea glutinosa seeds for removal of methylene blue: Facile preparation, characterization, and adsorption properties.

In this study, natural core-shell structure activated carbon beads (ACBs) from Litsea glutinosa seeds were successfully produced, characterized, and applied for adsorption of methylene blue (MB). The ACBs were prepared using single-step carbonization-activation with NaHCO3 at the optimized activation temperature, time, and activating agent concentration of 450 °C, 60 min, and 5%, respectively. Batch experiments were performed to determine the optimum adsorption conditions, suitable kinetic and isotherm models, and thermodynamic parameters for the adsorption of MB onto ACBs. The results showed that the ACBs were displayed as highly porous natural core-shell spheres with a diameter of about 5 mm. The adsorption of MB dye on ACBs was a spontaneous endothermic process, followed the Langmuir isotherm and the pseudo-second-order kinetic models with the rate-controlling step of both external diffusion and intra-particle diffusion. At the optimum conditions (pH of 9, the contact time of 10 h, the temperature of 40 °C, and an adsorbent dosage of 6 g/L), the maximum adsorption capacity reached 29.03 mg/g. The thermal method turned out to be more suitable for regenerating ACBs compared to the chemical method. The ACBs exhibited high reusability and stability, its adsorption efficiency could maintain more than 90% after five consecutive cycles of use. The electrostatic attraction, π-π interaction, hydrogen bonding, and pore-filling were identified as primary contributions to the adsorption mechanism. The overall results revealed that the ACBs could be used as a potential adsorbent for removing MB from water media.

Nano encapsulated novel compound SA-10 with therapeutic activity in both acute and chronic murine hindlimb ischemia models.

The production dysregulation of reactive oxygen species (ROS) and nitric oxide (NO) in ischemic tissues results in endothelial dysfunction, hyperinflammation and poor blood circulation. Here, we report a hybrid molecule, SA-10 with both NO donating and ROS scavenging abilities that demonstrated potent cytoprotection and tube formation activity in endothelial cells under H2O2-induced oxidative stress. SA-10 loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SA-10 NPs) were delivered intramuscularly (IM) to two murine hindlimb ischemia models. In the acute mode ischemia/reperfusion (I/R), the muscle damage, hyperinflammation, and lung edema were significantly reduced 3 days post-dose while in the chronic ischemia model, significant improvement of blood perfusion and physical endurance was observed over 30 days (P < 0.05). Elderly patients with acute and chronic limb ischemia have limited options for surgical or endovascular interventions, so we anticipate that a product like SA-10 NPs has potential as one of the therapeutic alternatives to surgery.

Enzyme-Assisted Fucoidan Extraction from Brown Macroalgae Fucus distichus subsp. evanescens and Saccharina latissima.

Fucoidans from brown macroalgae (brown seaweeds) have different structures and many interesting bioactivities. Fucoidans are classically extracted from brown seaweeds by hot acidic extraction. Here, we report a new targeted enzyme-assisted methodology for fucoidan extraction from brown seaweeds. This enzyme-assisted extraction protocol involves a one-step combined use of a commercial cellulase preparation (Cellic®CTec2) and an alginate lyase from Sphingomonas sp. (SALy), reaction at pH 6.0, 40 °C, removal of non-fucoidan polysaccharides by Ca2+ precipitation, and ethanol-precipitation of crude fucoidan. The workability of this method is demonstrated for fucoidan extraction from Fucus distichus subsp. evanescens (basionym Fucus evanescens) and Saccharina latissima as compared with mild acidic extraction. The crude fucoidans resulting directly from the enzyme-assisted method contained considerable amounts of low molecular weight alginate, but this residual alginate was effectively removed by an additional ion-exchange chromatographic step to yield pure fucoidans (as confirmed by 1H NMR). The fucoidan yields that were obtained by the enzymatic method were comparable to the chemically extracted yields for both F. evanescens and S. latissima, but the molecular sizes of the fucoidans were significantly larger with enzyme-assisted extraction. The molecular weight distribution of the fucoidan fractions was 400 to 800 kDa for F. evanescens and 300 to 800 kDa for S. latissima, whereas the molecular weights of the corresponding chemically extracted fucoidans from these seaweeds were 10-100 kDa and 50-100 kDa, respectively. Enzyme-assisted extraction represents a new gentle strategy for fucoidan extraction and it provides new opportunities for obtaining high yields of native fucoidan structures from brown macroalgae.

'Come into the fold': A comparative analysis of bacterial redox enzyme maturation protein members of the NarJ subfamily.

Redox enzyme maturation proteins (REMPs) are system-specific chaperones required for the maturation of complex iron sulfur molybdoenzymes that are important for anaerobic respiration in bacteria. Although they perform similar biological roles, REMPs are strikingly different in terms of sequence, structure, systems biology, and type of terminal electron acceptor that it supports for growth. Here we critically dissect current knowledge pertaining to REMPs of the nitrate reductase delta superfamily, specifically recognized in Escherichia coli to include NarJ, NarW, TorD, DmsD, and YcdY, also referred to as the NarJ REMP subfamily. We show that NarJ subfamily members share sequence homology and similar structural features as revealed by alignments performed on structurally characterized REMPs. We include an updated phylogenetic analysis of subfamily members, justifying their classification in this subfamily. The structural and functional roles of each member are presented herein and these discussions suggest that although NarJ subfamily members are related in sequence and structure, each member demonstrates remarkable uniqueness, validating the concept of system-specific chaperones.

Highly sensitive real-time in vivo imaging of an influenza reporter virus reveals dynamics of replication and spread.

The continual public health threat posed by the emergence of novel influenza viruses necessitates the ability to rapidly monitor infection and spread in experimental systems. To analyze real-time infection dynamics, we have created a replication-competent influenza reporter virus suitable for in vivo imaging. The reporter virus encodes the small and bright NanoLuc luciferase whose activity serves as an extremely sensitive readout of viral infection. This virus stably maintains the reporter construct and replicates in culture and in mice with near-native properties. Bioluminescent imaging of the reporter virus permits serial observations of viral load and dissemination in infected animals, even following clearance of a sublethal challenge. We further show that the reporter virus recapitulates known restrictions due to host range and antiviral treatment, suggesting that this technology can be applied to studying emerging influenza viruses and the impact of antiviral interventions on infections in vivo. These results describe a generalizable method to quickly determine the replication and pathogenicity potential of diverse influenza strains in animals.

Superior mesenteric artery blood flow velocities following medical treatment of a patent ductus arteriosus.

We examined superior mesenteric artery blood flow velocity in response to feeding in infants randomized to trophic feeds (n = 16) or nil per os (n = 18) during previous treatment for patent ductus arteriosus. Blood flow velocity increased earlier in the fed infants, but was similar in the 2 groups at 30 minutes after feeding.

Synthesis of fluorophore-tagged xylosides that prime glycosaminoglycan chains.

Biosynthesis and functions of glycosaminoglycan (GAG) chains are complex and remain elusive. To better understand the factors that regulate the biosynthesis and functions, fluorophore-tagged xylosides carrying two different linkages between fluorophore and xylose residue were synthesized and evaluated for their ability to prime GAG chains such as heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS) in various cell lines. These in vitro studies resulted in the identification of fluorophore-tagged xylosides that prime high molecular weight GAG chains. Primed GAG chains carrying a fluorophore group has several advantages for studying the factors that regulate the biosynthesis, analyzing intact fine structures at low detection limits, and setting the stage for studying structure-function relations of GAG chains of cellular origin.

Immunogenicity of Enhanced Influenza Vaccines Against Mismatched Influenza Strains in Older Adults: A Review of Randomized Controlled Trials.

Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza-related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality. The immunogenicity of enhanced vaccines against heterologous A(H3N2) strains has been examined in nine studies to date. In six studies, an enhanced, licensed MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) consistently increased heterologous antibody titers relative to standard influenza vaccine, with evidence of a broad heterologous immune response across multiple genetic clades. In one study, licensed high-dose trivalent inactivated influenza vaccine (HD-IIV3) also induced higher heterologous antibody titers than standard influenza vaccine. In a study comparing a higher dose licensed quadrivalent recombinant influenza vaccine (RIV4) with HD-IIV3 and aIIV3, no significant differences in antibody titers against a heterologous strain were observed, although seroconversion rates were higher with RIV4 versus comparators. With the unmet medical need for improved influenza vaccines, the paucity of studies especially with enhanced vaccines covering mismatched strains highlights a need for further investigation of cross-protection in older adults.

Fluorine-18-labelled Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography or Magnetic Resonance Imaging to Diagnose and Localise Prostate Cancer. A Prospective Single-arm Paired Comparison (PEDAL).

BACKGROUND AND OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) of the prostate is used for prostate cancer diagnosis. However, mpMRI has lower sensitivity for small tumours. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) offers increased sensitivity over conventional imaging. This study aims to determine whether the diagnostic accuracy of 18F-DCFPyL PSMA-PET/CT was superior to that of mpMRI for detecting prostate cancer (PCa) at biopsy. METHODS: Between 2020 and 2021, a prospective multicentre single-arm phase 3 imaging trial enrolled patients with clinical suspicion for PCa to have both mpMRI and PSMA-PET/CT (thorax to thigh), with reviewers blinded to the results of other imaging. Multiparametric MRI was considered positive for Prostate Imaging Reporting and Data System (PIRADS) 3-5. PSMA-PET/CT was assessed quantitatively (positive maximum standardised uptake value [SUVmax] >7) and qualitatively (five-point lexicon of certainty). Patients underwent targeted and systematic biopsy, with the technique at the discretion of the treating urologist. Clinically significant PCa (csPCa) was defined as International Society of Urological Pathology grade group (GG) ≥2. The primary outcome was the diagnostic accuracy for detecting PCa, reported as sensitivity, specificity, negative predictive value (NPV), and area under the curve (AUC) of the receiver operating curve. The secondary endpoints included a comparison of the diagnostic accuracy for detecting csPCa, assessing gains in combining PMSA-PET/CT with mpMRI to mpMRI alone. KEY FINDINGS AND LIMITATIONS: Of the 236 patients completing both mpMRI and PSMA-PET/CT, 184 (76.7%) had biopsy. Biopsy histology was benign (n = 73), GG 1 (n = 27), and GG ≥2 (n = 84). The diagnostic accuracy of mpMRI for detecting PCa (AUC 0.76; 95% confidence interval [CI] 0.69, 0.82) was higher than that of PSMA-PET/CT (AUC 0.63; 95% CI 0.56, 0.70, p = 0.03). The diagnostic accuracy of mpMRI for detecting csPCa (AUC 0.72; 95% CI 0.67, 0.78) was higher than that of PSMA-PET/CT (AUC 0.62; 95% CI 0.55, 0.69) but not statistically significant (p = 0.27). A combination of PSMA-PET/CT and mpMRI showed excellent sensitivity (98.8%, 95% CI 93.5%, 100%) and NPV (96%, 95% CI 79.6%, 99.9%) over mpMRI alone (86.9% and 80.7%, respectively, p = 0.01). Thirty-two patients (13.6%) had metastatic disease. They tended to be older (68.4 vs 65.1 yr, p = 0.023), and have higher prostate-specific antigen (PSA; median PSA 9.6 vs 6.2ng/ml, p < 0.001) and abnormal prostate on digital rectal examination (78.2% vs 44.1%, p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: Multiparametric MRI had superior diagnostic accuracy to PSMA-PET/CT for detecting PCa, though the difference is not significant in case of csPCa detection. A combination of mpMRI and PSMA-PET/CT showed improved sensitivity and NPV. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. PATIENT SUMMARY: In this trial, we compared the ability of 18F-labelled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) with that of multiparametric magnetic resonance imaging (mpMRI) to diagnose prostate cancer by biopsy in a prostate-specific antigen screening population. We found that MRI was superior to PSMA to diagnose prostate cancer, though there was no difference in ability to diagnose clinically significant prostate cancer. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. Combining MRI with PSMA-PET increases the negative predictive value over MRI alone and may help men avoid invasive prostate biopsy.

The hydrophobic region of the DmsA twin-arginine leader peptide determines specificity with chaperone DmsD.

The system specific chaperone DmsD plays a role in the maturation of the catalytic subunit of dimethyl sulfoxide (DMSO) reductase, DmsA. Pre-DmsA contains a 45-amino acid twin-arginine leader peptide that is important for targeting and translocation of folded and cofactor-loaded DmsA by the twin-arginine translocase. DmsD has previously been shown to interact with the complete twin-arginine leader peptide of DmsA. In this study, isothermal titration calorimetry was used to investigate the thermodynamics of binding between synthetic peptides composed of different portions of the DmsA leader peptide and DmsD. Only those peptides that included the complete and contiguous hydrophobic region of the DmsA leader sequence were able to bind DmsD with a 1:1 stoichiometry. Each of the peptides that were able to bind DmsD also showed some α-helical structure as indicated by circular dichroism spectroscopy. Differential scanning calorimetry revealed that DmsD gained very little thermal stability upon binding any of the DmsA leader peptides tested. Together, these results suggest that a portion of the hydrophobic region of the DmsA leader peptide determines the specificity of binding and may produce helical properties upon binding to DmsD. Overall, this study demonstrates that the recognition of the DmsA twin-arginine leader sequence by the DmsD chaperone shows unexpected rules and confirms further that the biochemistry of the interaction of the chaperone with their leaders demonstrates differences in their molecular interactions.