Search Results (34)

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in diagnosis and management. Methods: A systematic review of immunohistochemical markers of RCC studies published between 1990 and 2019 was undertaken to select candidate biomarkers of RCC. Immunohistochemical staining of 73 clear cell RCC tumors and paired normal tissue was undertaken using selected markers. Semi-quantitative and quantitative analysis of staining intensity between paired samples was undertaken to evaluate utility as potential biomarkers, using Chi-square tests and paired t-tests for analysis. As an exploratory analysis, staining intensity was also compared on clinical/demographic variables using linear and logistic regression. Results: There were 123 candidate biomarkers identified in 91 studies. Four candidate markers were selected for further investigation: aminopeptidase A (APA)/cluster of differentiation (CD)249, aminopeptidase N (APN)/CD13, gamma-glutamyl transferase (GGT), and neuron-specific enolase (NSE). APA, GGT, and APN all demonstrated reduced staining intensity in the tumor compared with normal tissue (p < 0.001 for all). NSE demonstrated a statistically significant increase in expression in tumor compared with normal tissue (p < 0.001), and this was more pronounced in patients aged >60 years (p = 0.038). Conclusions: The utility of APA, APN, and GGT as diagnostic biomarkers in clear cell RCC is limited. NSE may have some role as a biomarker for clear cell RCC, particularly among older patients; however, further investigation is required. Full article

Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) compared to sunitinib in the pivotal Checkmate 214 trial of metastatic renal cell carcinoma (mRCC) with International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk disease. We evaluated the efficacy and toxicity of ipi/nivo in older and frailer populations in a real-world mRCC cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N = 551) treated with first-line ipi/nivo from the Canadian Kidney Cancer information system (CKCis) database from January 2014 to December 2021. A comparison was made between outcomes and toxicity in patients 1. <70 versus (vs.) ≥70 yo, 2. <75 vs. ≥75 yo, and 3. KPS ≥70 vs. <70 yo. OS, progression-free survival (PFS), and time to treatment failure (TTF) were calculated by Kaplan–Meier analysis. Log-rank tests were used for comparison between groups. Results: Ipi/nivo treatment had no impact on survival outcomes or toxicity for patients >70 yo and >75 yo when controlled for IMDC. However, when comparing patients with KPS > 70 vs. KPS < 70, patients with a poor performance status had decreased median OS at 54.5 m vs. 10.8 m (p-value < 0.0001) and PFS at 11.6 vs. 3.1 m (p-value < 0.0001). Conclusions: The use of ipi/nivo in mRCC demonstrated similar survival outcomes and toxicity in an older patient population. In patients with a poor performance status, it was associated with inferior OS and PFS. We believe that ipi/nivo is a reasonable treatment option for these patient populations, particularly in older patients. Full article

Background: Special low-protein foods are essential in the dietary treatment of phenylketonuria (PKU). In the UK, these are available on prescription through the General Practitioners (GPs) and distributed via nutritional home delivery companies or pharmacies. Methods: A 58-item online non-validated semi-structured questionnaire was emailed to British Inherited Metabolic Disease Group (BIMDG) dietitians and dietetic support workers (DSW)/administrators working in PKU to ascertain the main system issues and errors with the supply of low-protein prescription foods (LPPF). Results: 73% (n = 53/73) of dietitians and 72% (n = 18/25) of DSW/administrators responded. A total of 80 questionnaires (representing 44 paediatric and 36 adult PKU centres) were completed. A total of 50% (n = 40/80) of respondents reported patient/caregiver problems accessing LPPF at least weekly. The most common problems were unavailable products (82%), missing LPPF in deliveries (79%), and delayed deliveries (66%). For 64% of respondents, >25% of their patients had recurring problems accessing LPPF, and 69% of respondents spent ≥1 h/week and 11% >5 h/week correcting LPPF patient supply issues. The most common foods patients experienced supply issues with were bread (96%), pasta/rice (41%) and milk replacements (35%). This was associated with GP prescription errors (65%), LPPF prescriptions sent to incorrect dispensers/suppliers (60%), and manufacturer supply issues (54%). Problems with patients/caregivers included not ordering LPPF in a timely way (81%), not responding to messages from home delivery companies (73%) and poor understanding of the ordering process (70%). The majority (93%) of respondents reported that prescription issues impacted their patients’ blood Phe control. Suggestions for improving access to LPPF included centralisation of the system to one supplier (76%) and apps for ordering LPPF (69%). Conclusions: The supply of LPPF for PKU in the UK is problematic; it may adversely affect the ability of patients to adhere to dietary management, and a review investigating patient access to LPPF is urgently required. Full article

Introduction: Patients receiving biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatological conditions are at an increased risk of serious, potentially life-threatening, infection. However, the incidence, aetiology, and clinical course of serious infection in patients receiving b/tsDMARDs in tropical settings are incompletely defined. Methods: We retrospectively reviewed all patients with rheumatoid arthritis receiving b/tsDMARDs between October 2012 and October 2021, at Cairns Hospital in tropical Australia. The incidence, aetiology, and clinical course of serious infections (those requiring admission to hospital or parenteral antibiotics) were determined. Results: 310 patients had 1468 patient years of b/tsDMARD therapy during the study period; 74/310 (24%) had 147 serious infections translating to an overall risk of 10.0 episodes of serious infection per 100 patient years. The respiratory tract (50/147, 34%) and skin (37/147, 25%) were the most frequently affected sites. A pathogen was identified in 59/147 (40%) episodes and was most commonly Staphylococcus aureus (24/147, 16%). Only 2/147 (1%) were confirmed “tropical infections”: 1 case of Burkholderia pseudomallei and 1 case of mixed B. pseudomallei and community-acquired Acinetobacter baumannii infection. Overall, 13/147 (9%) episodes of serious infection required Intensive Care Unit admission (0.9 per 100-patient years of b/tsDMARD therapy) and 4/147 (3%) died from their infection (0.3 per 100-patient years of b/tsDMARD therapy). The burden of comorbidity and co-administration of prednisone were the strongest predictors of death or a requirement for ICU admission. Conclusions: The risk of serious infection in patients taking b/tsDMARDs in tropical Australia is higher than in temperate settings, but this is not explained by an increased incidence of traditional tropical pathogens. Full article

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13–0.68) and CN-ST (HR 0.68, CI 0.47–0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26–0.77) and CN-ST (HR 0.9, CI 0.68–1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN. Full article

The aim of this pilot study was to evaluate and compare bioavailability and safety of two Vitamin D₃ formulations (softgels) in healthy adults, at single daily doses of 1000 and 2500 IU, over a 60-day period. A total of 69 participants were initially screened for eligibility in a double-blind randomized study with a four-arm parallel design; 35 participants were randomized to treatment groups: (1) standard Vitamin D₃ 1000 IU (STD1000), (2) micellar Vitamin D₃ 1000 IU (LMD1000), (3) standard Vitamin D₃ 2500 IU (STD2500), and (4) micellar Vitamin D₃ 2500 IU (LMD2500). Serum Vitamin D concentrations were determined through calcifediol [25(OH)D] at baseline (=before treatment), at day 5, 10, and 15 (=during treatment), at day 30 (=end of treatment), and at day 45 and 60 (=during follow-up/post treatment). Safety markers and minerals were evaluated at baseline and at day 30 and day 60. The pharmacokinetic parameters with respect to iAUC were found to be significantly different between LMD1000 vs. STD1000: iAUC(5–60): 992 ± 260 vs. 177 ± 140 nmol day/L; p < 0.05, suggesting up to 6 times higher Vitamin D₃ absorption of LMD when measured incrementally. During follow-up, participants in the LMD1000 treatment group showed approx. 7 times higher Vitamin D₃ concentrations than the STD1000 group (iAUC(30–60): 680 ± 190 vs. 104 ± 91 nmol day/L; p < 0.05). However, no significant differences were found between the pharmacokinetics of the higher dosing groups STD2500 and LMD2500. No significant changes in serum 1,25(OH)₂D concentrations or other biochemical safety markers were detected at day 60; no excess risks of hypercalcemia (i.e., total serum calcium > 2.63 mmol/L) or other adverse events were identified. LMD, a micellar delivery vehicle for microencapsulating Vitamin D₃ (LipoMicel^®), proved to be safe and only showed superior bioavailability when compared to standard Vitamin D at the lower dose of 1000 IU. This study has clinical trial registration: NCT05209425. Full article

Dental caries is one of the most prevalent chronic diseases globally in both children and adults. This study investigated the potential of industrial sweet orange waste extracts (ISOWE) as a substitute for chlorhexidine (CHX) in managing dental caries. First, the cytotoxicity of ISOWE (40, 80, 120 mg/mL) and CHX (0.1 and 0.2%) on buccal epithelial cells was determined. ISOWE exhibited no overall toxicity, whereas CHX strongly affected cell viability. The combination of ISOWE and CHX significantly enhanced cell proliferation compared to CHX alone. Next, the antimicrobial efficacy of ISOWE, CHX, and their combination was assessed against a 7-day complex biofilm model inoculated with oral samples from human volunteers. CHX exhibited indiscriminate antimicrobial action, affecting both pathogenic and health-associated oral microorganisms. ISOWE demonstrated lower antimicrobial efficacy than CHX but showed enhanced efficacy against pathogenic species while preserving the oral microbiome’s balance. When applied to a cariogenic biofilm, the combined treatment of ISOWE with 0.1% CHX showed similar efficacy to 0.2% CHX treatment alone. Overall, the findings suggest that ISOWE is a promising natural anti-cariogenic agent with lower toxicity and enhanced selectivity for pathogenic species compared to CHX. Full article

Berberine is a plant-origin quaternary isoquinoline alkaloid with a vast array of biological activities, including antioxidant and blood-glucose- and blood-lipid-lowering effects. However, its therapeutic potential is largely limited by its poor oral bioavailability. The aim of this study was to investigate the in vitro solubility and Caco-2 cell permeability followed by pharmacokinetic profiling in healthy volunteers of a new food-grade berberine delivery system (i.e., Berberine LipoMicel^®). X-ray diffractometry (XRD), in vitro solubility, and Caco-2 cell permeability indicated higher bioavailability of LipoMicel Berberine (LMB) compared to the standard formulation. Increased aqueous solubility (up to 1.4-fold), as well as improved Caco-2 cell permeability of LMB (7.18 × 10⁻⁵ ± 7.89 × 10⁻⁶ cm/s), were observed when compared to standard/unformulated berberine (4.93 × 10⁻⁶ ± 4.28 × 10⁻⁷ cm/s). Demonstrating better uptake, LMB achieved significant increases in AUC_0–24 and C_max compared to the standard formulation (AUC: 78.2 ± 14.4 ng h/mL vs. 13.4 ± 1.97 ng h/mL, respectively; p < 0.05; C_max: 15.8 ± 2.6 ng/mL vs. 1.67 ± 0.41 ng/mL) in a pilot study of healthy volunteers (n = 10). No adverse reactions were reported during the study period. In conclusion, LMB presents a highly bioavailable formula with superior absorption (up to six-fold) compared to standard berberine formulation and may, therefore, have the potential to improve the therapeutic efficacy of berberine. The study has been registered on ClinicalTrials.gov with Identifier NCT05370261. Full article

Flood modelling is essential for addressing a range of scientific and engineering challenges. In recent years, the high computational demands of solving shallow water equations numerically have led researchers to explore machine-learning-based emulators for predicting floods and flood risk. Specifically, the proliferation of convolutional neural networks in solving different scientific problems has encouraged researchers to investigate their applicability in flood modelling. Most of these studies, however, have focused on specific locations or hydrological conditions, meaning that their findings may not be directly applicable to other situations without additional data and further training. We present here a U-Net model, a popular deep learning algorithm, which has the capacity to approximate maximum flood depths across multiple return periods while maintaining catchment generalizability. The model was trained using the outputs from a 2D hydraulic model (JFlow) to predict maximum water depths for a set of rainfall return periods (20, 100 and 1000 years). The pre-trained model was then applied to estimate depths in three unseen catchment areas. Our results demonstrate that U-Net can be used to approximate water depths in previously unseen catchments with significantly less computational time compared to the 2D model. Full article

Vitamin D is an essential nutrient with important immunomodulatory properties. As a fat-soluble compound, Vitamin D (and its D₃ form) is immiscible with water, which presents challenges to absorption. In an in vitro setting, the current study characterizes novel micellar formulations of Vitamin D₃ designed to improve absorption. Techniques used to evaluate and compare the micellar formulations against a non-micellar formula include the following: cryo-SEM to determine morphology; laser diffraction to determine particle size and distribution; zeta potential to determine stability of the particles; solubility assays to determine solubility in water and gastrointestinal media; and Caco-2 cell monolayers to determine intestinal permeability. Results show advantageous features (particle size range in the low micrometres with an average zeta potential of −51.56 ± 2.76 mV), as well as significant improvements in intestinal permeability, in one optimized micellar formula (LipoMicel^®). When introduced to Caco-2 cells, LipoMicel’s permeability was significantly better than the control (p < 0.01; ANOVA). Findings of this study suggest that the novel micellar form of Vitamin D₃ (LipoMicel) has the potential to promote absorption of Vitamin D₃. Thus, it can serve as a promising candidate for follow-up in vivo studies in humans. Full article

Diabetic foot infections (DFIs) are a common complication of diabetes; however, there is clinical uncertainty regarding the optimal antimicrobial selection. The aim of this review was to critically evaluate the recent systematic reviews on the efficacy and safety of systemic (parenteral or oral) antimicrobials for DFI. Medline, Embase, CENTRAL, and CINAHL databases and the PROSPERO register were searched from January 2015 to January 2023. Systematic reviews with or without meta-analyses on systemic antimicrobials for DFI, with outcomes of clinical infection resolution or complications, were included. Of the 413 records identified, 6 systematic reviews of 29 individual studies were included. Heterogeneity of individual studies precluded meta-analysis, except for ertapenem versus piperacillin–tazobactam (RR 1.07, 95% CI [0.96–1.19]) and fluoroquinolones versus piperacillin–tazobactam (RR 1.03, 95% CI [0.89–1.20]) in one review. The application of the AMSTAR-2 tool determined two reviews to be of high quality. There was no statistical difference in the clinical resolution of infections for 24 different antimicrobial regimens (penicillins, cephalosporins, carbapenems, fluoroquinolones, vancomycin, metronidazole, clindamycin, linezolid, daptomycin, and tigecycline). However, tigecycline did not meet non-inferiority against ertapenem ± vancomycin (absolute difference −5.5%, 95% CI [−11.0–0.1]) and was associated with a higher incidence of adverse drug events. There is minimal systematic review evidence to suggest one regimen is superior to another for DFI. Full article

This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22–2.12] and 1.46 [95%CI 1.09–1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15–6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02–4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59–10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals. Full article

Extrusion-based 4D-printing, which is an emerging field within additive manufacturing, has enabled the technical transfer of bioinspired self-shaping mechanisms by emulating the functional morphology of motile plant structures (e.g., leaves, petals, capsules). However, restricted by the layer-by-layer extrusion process, much of the resulting works are simplified abstractions of the pinecone scale’s bilayer structure. This paper presents a new method of 4D-printing by rotating the printed axis of the bilayers, which enables the design and fabrication of self-shaping monomaterial systems in cross sections. This research introduces a computational workflow for programming, simulating, and 4D-printing differentiated cross sections with multilayered mechanical properties. Taking inspiration from the large-flowered butterwort (Pinguicula grandiflora), which shows the formation of depressions on its trap leaves upon contact with prey, we investigate the depression formation of bioinspired 4D-printed test structures by varying each depth layer. Cross-sectional 4D-printing expands the design space of bioinspired bilayer mechanisms beyond the XY plane, allows more control in tuning their self-shaping properties, and paves the way toward large-scale 4D-printed structures with high-resolution programmability. Full article

The current study evaluated the antibacterial properties of industrial sweet orange waste extracts (ISOWEs), which are a rich source of flavonoids. The ISOWEs exhibited antibacterial activity towards the dental cariogenic pathogens Streptococcus mutans and Lactobacillus casei with 13.0 ± 2.0 and 20.0 ± 2.0 mg/mL for MIC (minimum inhibitory concentration) and 37.7 ± 1.5 and 43.3 ± 2.1 mg/mL for MBC (minimum bactericidal concentration), respectively. When evaluated in a 7-day dual-species oral biofilm model, ISOWEs dose-dependently reduced the viable bacteria count, and demonstrated strong synergistic effects when combined with the anti-septic chlorhexidine (at 0.1 and 0.2%). Similarly, confocal microscopy confirmed the anti-cariogenic properties of ISOWEs, alone and in combination with chlorhexidine. The citrus flavonoids contributed differently to these effects, with the flavones (nobiletin, tangeretin and sinensetin) demonstrating significantly lower MICs and MBCs compared to the flavanones hesperidin and narirutin. In conclusion, our study demonstrated the potential of citrus waste as a currently underutilised source of flavonoids for antimicrobial applications, such as in dental health. Full article

Magnesium doped Amorphous Calcium Carbonate was synthesised from precursor solutions containing varying amounts of calcium, magnesium, H₂O and D₂O. The Mg/Ca ratio in the resultant Amorphous Calcium Carbonate was found to vary linearly with the Mg/Ca ratio in the precursor solution. All samples crystallised as aragonite. No Mg was found in the final aragonite crystals. Changes in the Mg to Ca ratio were found to only marginally effect nucleation rates but strongly effect crystal growth rates. These results are consistent with a dissolution-reprecipitation model for aragonite formation via an Amorphous Calcium Carbonate intermediate. Full article