Comparison of Composite Measure Remission Targets in Psoriatic Arthritis

Objective To identify 1) which composite measure is the most stringent target of remission; and 2) which disease component target proves the most difficult to achieve in the different states of MDA, CPDAI, DAPSA and cDAPSA in patients with PsA. Methods 258 PsA patients were recruited. Disease remission was evaluated comparing 4 different composite measures and using remission cut-offs as previously proposed (VLDA (MDA 7/7), CPDAI ≤2, DAPSA ≤4, cDAPSA ≤4). Results Patients met VLDA criteria in 9.0% of visits, DAPSA remission in 19.8%, cDAPSA remission in 23.4% and CPDAI remission in 30.2%. Of 258 patients, MDA criteria (≥5/7) were fulfilled in 46.5%. Of those in MDA, VLDA criteria were reached in 25.0%. Patients met the pain VAS target in 57.5 % of visits when they were in MDA, 43.3% when in LDA (MDA 5-6/7) and 44.8% when in CPDAI remission. Multivariate regression analysis revealed that pain VAS was the least likely target to be achieved. Patients with inflammatory-type back pain had significantly higher pain scores; furthermore, a significant relationship was seen between BASDAI and pain VAS. Conclusion Based on our analysis, VLDA proved the most stringent target of disease remission in PsA compared to CPDAI, DAPSA and cDAPSA. The pain VAS target of ≤1.5 cm was the most difficult component to achieve. CPDAI ≤2 was found to be the least stringent remission target; however, measurements of axial involvement, which contributed to the elevated pain VAS score in patients not achieving VLDA, were only included as a domain in CPDAI.

A CRISPR-Cas autocatalysis-driven feedback amplification network for supersensitive DNA diagnostics

Artificial nucleic acid circuits with precisely controllable dynamic and function have shown great promise in biosensing, but their utility in molecular diagnostics is still restrained by the inability to process genomic DNA directly and moderate sensitivity. To address this limitation, we present a CRISPR-Cas–powered catalytic nucleic acid circuit, namely, CRISPR-Cas–only amplification network (CONAN), for isothermally amplified detection of genomic DNA. By integrating the stringent target recognition, helicase activity, and trans-cleavage activity of Cas12a, a Cas12a autocatalysis-driven artificial reaction network is programmed to construct a positive feedback circuit with exponential dynamic in CONAN. Consequently, CONAN achieves one-enzyme, one-step, real-time detection of genomic DNA with attomolar sensitivity. Moreover, CONAN increases the intrinsic single-base specificity of Cas12a, and enables the effective detection of hepatitis B virus infection and human bladder cancer–associated single-nucleotide mutation in clinical samples, highlighting its potential as a powerful tool for disease diagnostics.

Assessing the Healthy Food Partnership’s Proposed Nutrient Reformulation Targets for Foods and Beverages in Australia

Non-communicable diseases (NCDs) are the leading cause of mortality and morbidity worldwide. Unhealthy diets are one of four main behavioral risk factors contributing to the majority of NCDs. To promote healthy eating and reduce dietary risks, the Australian Commonwealth Government established the Healthy Food Partnership (HFP). In 2018, the HFP consulted on proposed nutrient reformulation targets for 36 food categories to improve the overall quality of the food supply. This study assessed whether the proposed targets were feasible and appropriate. The HFP used a five-step approach to inform the proposed targets. We replicated and extended this approach using a different nutrient composition database (FoodSwitch). Products in FoodSwitch were mapped to the proposed HFP targets. The proportion of products meeting each target was calculated and the FoodSwitch data were compared with HFP data to determine whether the proposed target nutrient levels were appropriate or whether a more stringent target was feasible. Products from the FoodSwitch database (10,599) were mapped against the proposed HFP categories: 8434 products across 30 categories for sodium, 2875 products across seven categories for sugar, and 612 products across five categories for saturated fat. The analyses revealed that 14 of 30 proposed HFP targets for sodium, one of seven targets for sugar, and one of five targets for saturated fat were feasible and appropriate. For the remaining 26 reformulation targets, the results indicate that these target levels could be more stringent and alternative targets are proposed. The draft HFP targets are feasible but the majority are too conservative. If Australia is to meet its commitment to a 30 per cent reduction in the average population salt intake by 2025, these targets could be implemented as interim targets to be reached within two years. However, the opportunity exists to improve the food supply and strengthen the HFP’s population health impact by adopting more ambitious and incremental targets. Reformulation programs should be prioritized and closely monitored as part of a coordinated, multi-faceted national food and nutrition strategy.

Altered microRNA and target gene expression related to Tetralogy of Fallot

MicroRNAs (miRNAs) play an important role in guiding development and maintaining function of the human heart. Dysregulation of miRNAs has been linked to various congenital heart diseases including Tetralogy of Fallot (TOF), which represents the most common cyanotic heart malformation in humans. Several studies have identified dysregulated miRNAs in right ventricular (RV) tissues of TOF patients. In this study, we profiled genome-wide the whole transcriptome and analyzed the relationship of miRNAs and mRNAs of RV tissues of a homogeneous group of 22 non-syndromic TOF patients. Observed profiles were compared to profiles obtained from right and left ventricular tissue of normal hearts. To reduce the commonly observed large list of predicted target genes of dysregulated miRNAs, we applied a stringent target prediction pipeline integrating probabilities for miRNA-mRNA interaction. The final list of disease-related miRNA-mRNA pairs comprises novel as well as known miRNAs including miR-1 and miR-133, which are essential to cardiac development and function by regulating KCNJ2, FBN2, SLC38A3 and TNNI1. Overall, our study provides additional insights into post-transcriptional gene regulation of malformed hearts of TOF patients.

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

ABSTRACTPharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy againstMycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC0–24) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates ofMycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for targetfAUC0–24/MIC ratios of ≥53 and ≥100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR)Mycobacterium tuberculosisstrains. Even with the less stringent target ratio of ≥53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.