LncRNA HULC augments high glucose-associated pancreatic cancer progression and drug resistance by enhancing YAP activity and autophagy.

BACKGROUND INFORMATION: One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is poorly understood. Our investigation delved into the impact of lncRNA highly upregulated in liver cancer (HULC) and its interaction with yes-associated protein (YAP) in regulating the fate of pancreatic ductal adenocarcinoma cells (PDAC) under HG-induced conditions. PDAC cells were cultured under normal or HG conditions. We thereafter measured the effect of HG on the viability of PDAC cells, their migration potential and drug resistance properties. The lncRNAs putatively dysregulated in PC and diabetes were shortlisted by bioinformatics analysis followed by wet lab validation of function. RESULTS: HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop. CONCLUSIONS: We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells. SIGNIFICANCE: Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.

Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome.

Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine's hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.

Risk and predictors of fractures in early rheumatoid arthritis - A long term follow up study of an inception cohort.

OBJECTIVES: To examine the risk of fractures in a cohort of patients with newly diagnosed rheumatoid arthritis (RA), compared to the background population, and predictors of fractures detectable early in RA. METHODS: An inception cohort of patients with RA (N = 233; 164 women/69 men, recruited 1995-2005) was evaluated according to a structured program, including repeated clinical assessments and measures of bone mineral density (BMD), from diagnosis to 10 years later. Matched population controls were identified using the national census register. Fractures through 2019 were identified based on ICD codes. Cox regression models were used to assess the risk of fractures in RA patients compared with controls, and for assessment of potential predictors for fractures in the RA population. RESULTS: RA patients had an increased risk of fractures (fully adjusted hazard ratio (HR) 1.52, 95 % CI 1.13; 2.06). In the RA cohort, high age, low body mass index, and low BMD were significant baseline predictors of future fractures in multivariate analyses, but baseline RA disease characteristics were not. Worse disability (i.e. higher Health Assessment Questionnaire (HAQ) scores) over time was significantly associated with increased risk of fractures (age-sex-adjusted HR 1.33 per SD, 95 % CI 1.09; 1.63) and there was an inverse association between BMD Z-scores over time and fractures. CONCLUSION: Patients with RA had higher risk of fractures than controls. Fracture risk was related to BMD at baseline and over time in patients with RA. In addition, worse disability (measured by HAQ) over time was associated with higher risk of fractures.

Targeting CERS6-AS1/FGFR1 axis as synthetic vulnerability to constrain stromal cells supported proliferation in Mantle cell lymphoma.

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL.

The role of interleukin-10 receptor alpha (IL10Rα) in Mycobacterium avium subsp. paratuberculosis infection of a mammary epithelial cell line.

BACKGROUND: Johne's disease is a chronic wasting disease caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease is highly contagious and MAP infection in dairy cattle can eventually lead to death. With no available treatment for Johne's disease, genetic selection and improvements in management practices could help reduce its prevalence. In a previous study, the gene coding interleukin-10 receptor subunit alpha (IL10Rα) was associated with Johne's disease in dairy cattle. Our objective was to determine how IL10Rα affects the pathogenesis of MAP by examining the effect of a live MAP challenge on a mammary epithelial cell line (MAC-T) that had IL10Rα knocked out using CRISPR/cas9. The wild type and the IL10Rα knockout MAC-T cell lines were exposed to live MAP bacteria for 72 h. Thereafter, mRNA was extracted from infected and uninfected cells. Differentially expressed genes were compared between the wild type and the IL10Rα knockout cell lines. Gene ontology was performed based on the differentially expressed genes to determine which biological pathways were involved. RESULTS: Immune system processes pathways were targeted to determine the effect of IL10Rα on the response to MAP infection. There was a difference in immune response between the wild type and IL10Rα knockout MAC-T cell lines, and less difference in immune response between infected and not infected IL10Rα knockout MAC-T cells, indicating IL10Rα plays an important role in the progression of MAP infection. Additionally, these comparisons allowed us to identify other genes involved in inflammation-mediated chemokine and cytokine signalling, interleukin signalling and toll-like receptor pathways. CONCLUSIONS: Identifying differentially expressed genes in wild type and ILR10α knockout MAC-T cells infected with live MAP bacteria provided further evidence that IL10Rα contributes to mounting an immune response to MAP infection and allowed us to identify additional potential candidate genes involved in this process. We found there was a complex immune response during MAP infection that is controlled by many genes.

N-Benzyl piperidine Fragment in Drug Discovery.

The N-benzyl piperidine (N-BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three-dimensional nature. Medicinal chemists frequently utilize the N-BP motif as a versatile tool to fine-tune both efficacy and physicochemical properties in drug development. It provides crucial cation-π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N-BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. We provide an overview of approved drugs, the clinical and preclinical pipeline, and discuss its utility for specific therapeutic targets and indications, along with potential challenges.

Unknotting tech neck by breaking the cycle of pain and disability: Comparing the impact of instrument assisted soft tissue mobilization on specific muscles and superficial back arm line.

BACKGROUND: Computer professionals often develop a forward head posture due to prolonged hours of computer use, leading to neck pain. Instrument-assisted soft tissue mobilization (IASTM), an advanced technique for treating myofascial trigger points, has become increasingly popular for addressing these musculoskeletal issues. OBJECTIVES: The study aimed to compare the effectiveness of IASTM mobilization on SBAL (superficial back arm line) and SM(specific muscles-upper trapezius, levator scapulae, and sternocleidomastoid) in managing chronic neck pain among computer professionals. PARTICIPANTS & METHODS: The study involved 62 computer professionals, randomly divided into two groups. Group A received IASTM on SBAL and group B received IASTM on SM for neck pain each receiving three sessions weekly for four weeks. Outcome variables like Neck Disability Index (NDI), NPRS(Neck Pain Rating Scale), Craniovertebral angle (CVA), and range of motion (ROM) for flexion, and side flexion (right & left side) were evaluated at baseline, 2 weeks and 4 weeks. RESULTS: Significant improvement in NPRS were observed in both the SBAL and SM groups after 2 weeks of IASTM, wth the SBAL group demonstrating greater improvement. At 4 weeks, IASTM on SBAL showed significantly higher improvements in NPRS, CVA, NDI, and flexion compared to the SM group. The repeated measures ANOVA indicated a significant main effect of both time and group, along with a significant interaction between time and group for all outcome variables, except for CVA. CONCLUSION: The study indicates that IASTM on SBAL may offer a more effective treatment for chronic neck pain in computer professionals compared to targeting specific muscles.

Adult Partial Anomalous Pulmonary Venous Connection: Case Reports (Including a Case of Scimitar Syndrome).

Partial anomalous pulmonary venous connection (PAPVC) is a congenital heart defect in which one or more pulmonary veins drain abnormally into the systemic venous circulation, leading to the development of pulmonary arterial hypertension. It can be supracardiac type, draining into the superior vena cava or right atrium (also called cardiac type) and infracardiac type with drainage into the inferior vena cava (IVC). We present two cases-supracardiac and infracardiac types of PAPVC in this case report.

Effects of pain education on disability, pain, quality of life, and self-efficacy in chronic low back pain: A randomized controlled trial.

BACKGROUND: Low back pain stands as a prevalent contributor to pain-related disability on a global scale. In addressing chronic low back pain (CLBP), there is a growing emphasis on incorporating psychological strategies into the management process. Among these, pain education interventions strive to reshape pain beliefs and mitigate the perceived threat of pain. This randomized controlled trial sought to assess the effects of pain education on various aspects, including pain levels, disability, quality of life, self-efficacy, and prognostic characteristics in individuals grappling with CLBP. METHODS: The clinical trial, retrospectively registered with the Clinical Trials Registry of India (CTRI/2021/08/035963), employed a two-arm parallel randomized design. Ninety-two participants with CLBP were randomly assigned to either the standard physiotherapy care with a pain education program or the control group. Both groups underwent a 6-week intervention. Assessment of pain intensity (using NPRS), disability (using RMDQ), self-efficacy (using the general self-efficacy scale), and well-being (using WHO 5I) occurred both before and after the 6-week study intervention. FINDINGS: Post-intervention score comparisons between the groups revealed that the pain education intervention led to a significant reduction in disability compared to the usual standard care at 6 weeks (mean difference 8.2, p < 0.001, effect size Cohen d = 0.75), a decrease in pain intensity (mean difference 3.5, p < 0.001, effect size Cohen d = 0.82), and an improvement in the well-being index (mean difference 13.7, p < 0.001, effect size Cohen d = 0.58). CONCLUSION: The findings suggest that integrating a pain education program enhances the therapeutic benefits of standard physiotherapy care for individuals dealing with chronic LBP. In conclusion, the clinical benefits of pain education become apparent when delivered in conjunction with standard care physiotherapy during the management of chronic low back pain.

Assessing muscle energy technique and foam roller self-myofascial release for low back pain management in two-wheeler riders.

Pain in the lower back is a major concern in today's era due to prolonged sitting in two-wheeler riders, mainly due to hamstring tightness. It also creates physical disability and impairment in activities of daily living. The study aimed to compare the efficacy of muscle energy technique (MET) and self-myofascial release (SMFR) using the foam roller on hamstring flexibility, dynamic balance, and physical disability amongst two-wheeler riders with chronic low back pain (LBP). Participants were randomized into two intervention groups, MET and SMFR using the envelope method, with each group having 20 participants. Hamstring flexibility and range of motion for knee extension and the lower back were assessed using the active knee extension test (AKE-L and AKE-R) and sit and reach test (SRT), while the dynamic balance was assessed by the star excursion balance test (SEBT) and physical disability by Roland-Morris Disability Questionnaire, (RMDQ). Measurements were taken at baseline and after 4 weeks of intervention. This study demonstrated that both SMFR using a foam roller and MET are effective in enhancing hamstring muscle flexibility, (SRT-F(1, 38) = 299.5, p < 0.001; AKE-R-F(1, 38) = 99.53, p < 0.001; AKE-L-F(1, 38) = 89.67, p < 0.001). Additionally, these techniques significantly improved dynamic balance in various directions, including anterior (ANT), anteromedial (AMED), medial (MED), posteromedial (PMED), posterior (POST), posterolateral (PLAT), lateral (LAT), and anterolateral (ALAT) directions (p < 0.01). Furthermore, there was a significant reduction in physical disability (RMDQ-F(1, 38) = 1307, p < 0.001), among two-wheeler riders suffering from chronic LBP. Compared to MET, SMFR using foam rollers was found to be more effective in enhancing hamstring flexibility, improving balance, and decreasing disability level on the RMDQ after 4 weeks.

A Study to Evaluate the Effect of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors on Oxidative Stress Parameters in Type 2 Diabetes Mellitus Patients.

Introduction Diabetes mellitus (DM) is a global health issue with 50 million diabetics currently residing in India. Hyperglycemia causes tissue damage due to mitochondrial overproduction of reactive oxygen species. Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) have shown a decrease in oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity in preclinical studies. However, there is a paucity of published clinical studies. Hence, this study was undertaken to evaluate the effect of co-administration of SGLT2i with other drugs on oxidative stress in type 2 DM (T2DM) patients. Methods A prospective, parallel, open-label study in T2DM patients attending endocrinology OPD was conducted for a period of 12 months. At the clinician's discretion, patients were grouped as SGLT2i as an add-on to standard drugs vs standard drugs alone. Blood samples were collected at baseline and at the end of 12 weeks to estimate malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels. Secondary parameters - glycemic indices and lipid profile - were estimated every four weeks. Results A total of 32 patients were enrolled in the study (16 per group). There was a significant decrease in MDA (p < 0.05) and NO (p < 0.01) and a highly significant increase in GSH (p < 0.001) at 12 weeks from baseline in the SGLT2i group. A reduction in fasting blood sugar (FBS) and post-prandial blood sugar (PPBS) and a 0.56% difference in HbA1c were also noted in the SGLT2i group. Significant lowering of low-density lipoprotein (LDL, p < 0.05) and elevation in HDL levels (p < 0.05) from baseline was seen in the SGLT2i group.  Conclusion Co-administration of SGLT2i with antidiabetic drugs demonstrated a significant effect in improving oxidative stress biomarkers and glycemic and lipid profiles among T2DM patients.

Navigating the Antiretroviral Therapy Switch Conundrum: Unveiling the Dilemma of Drug Resistance and Disease Progression in HIV/AIDS.

There is a need to establish consensus for harmonization in antiretroviral (ARV) therapy (ART) switch treatment strategy and address the dilemma that exists in terms of subpar immune response to therapy or an immunologic deterioration while on therapy. The purpose of this review is to identify the factors that contribute to ARV treatment failure, such as insufficient dosage, drug interactions, poor adherence, drug resistance, and poor medication absorption. It is crucial to adopt a more efficient strategy to address this challenging dilemma. After ARV treatment failure, the aim of therapy is virologic suppression, which targets plasma viral load below the limits of detection as assessed by very sensitive tests with lower limits of quantification of 20 to 75 RNA copies/ml. The therapeutic objectives when complete virologic suppression is not possible, should be to maintain or restore immunologic function, stop the progression of the clinical illness, and minimize the emergence of new drug resistance that could further restrict the options for ARV drugs. Treatment history and drug-resistance testing, including the findings of previous and ongoing resistance tests, should be considered while selecting ARV regimens. Hence, the treatment approach post-ARV failure can be personalized based on clinical, immunologic, virologic, or as a mix of the three domains on a case-to-case basis. The evaluation of projected ARV activity should be based on treatment history and previous resistance test findings.

Development of wafer-scale multifunctional nanophotonic neural probes for brain activity mapping.

Optical techniques, such as optogenetic stimulation and functional fluorescence imaging, have been revolutionary for neuroscience by enabling neural circuit analysis with cell-type specificity. To probe deep brain regions, implantable light sources are crucial. Silicon photonics, commonly used for data communications, shows great promise in creating implantable devices with complex optical systems in a compact form factor compatible with high volume manufacturing practices. This article reviews recent developments of wafer-scale multifunctional nanophotonic neural probes. The probes can be realized on 200 or 300 mm wafers in commercial foundries and integrate light emitters for photostimulation, microelectrodes for electrophysiological recording, and microfluidic channels for chemical delivery and sampling. By integrating active optical devices to the probes, denser emitter arrays, enhanced on-chip biosensing, and increased ease of use may be realized. Silicon photonics technology makes possible highly versatile implantable neural probes that can transform neuroscience experiments.

VCP Inhibition Augments NLRP3 Inflammasome Activation.

Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1ß by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored. Here, we demonstrate that the VCP inhibitors, DBeQ and ML240 elicit the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) when used as activation stimuli. Moreover, genetic inhibition of VCP or VCP chemical inhibition enhances lysosomal membrane damage and augments LLoME-associated NLRP3 inflammasome activation in BMDMs. Similarly, VCP inactivation also augments NLRP3 inflammasome activation mediated by aggregated alpha-synuclein fibrils and lysosomal damage. These data suggest that VCP is a participant in the complex regulation of NLRP3 inflammasome activation.

Use of Endodontic Procedures in Young Permanent Teeth.

Background: Regenerative endodontic procedures (REPs) have emerged as a promising treatment option for young permanent teeth with pulp necrosis, offering the potential for tissue repair and preservation. Materials and Methods: A retrospective analysis was conducted on a cohort of 30 patients aged 8 to 16 years with pulp necrosis in young permanent teeth. The patients underwent REPs, including disinfection, triple antibiotic paste application, and a coronal barrier. Clinical and radiographic data were collected at baseline and follow-up appointments at 6, 12, and 24 months. Radiographs were analyzed for root lengthening, apical closure, and resolution of periapical lesions. Results: The mean increase in root length after 24 months was 3.42 mm (SD ± 1.12 mm), and 90% of cases demonstrated complete apical closure. The overall success rate, defined as the absence of clinical symptoms and radiographic evidence of pathology, was 80. Conclusion: REPs show promising outcomes in young permanent teeth with pulp necrosis, promoting root development, and apical closure.

The prevalence of chronic obstructive pulmonary disease in patients with spondyloarthritis compared to the general population in the southernmost region of Sweden: a case-control study.

Spondyloarthritis (SpA) has been associated with comorbidities, e.g., cardiovascular disease. However, little is known about the relation between SpA and chronic obstructive pulmonary disease (COPD). The aim of the study was to compare the prevalence of COPD in SpA to the general population. Patients with prevalent SpA in Skåne, Sweden, on December 31, 2018, were identified based on diagnostic codes in a regional register on primary care, secondary outpatient care and inpatient care. Population-based controls (5 per SpA case) were matched for age, sex and municipality. The base case definition for COPD required at least two prior visits with a registered COPD diagnosis. Stricter definitions included dispensed prescriptions for COPD and a COPD diagnosis made by a specialist in lung medicine. The prevalence of COPD in patients with SpA and controls, overall and stratified by sex and age, and the corresponding prevalence ratios, were estimated. A total of 3571 patients with SpA (51% male, mean age 53 years) were compared to 17,855 matched controls. The prevalence of COPD in patients with SpA was 37.8/1000, with a prevalence ratio compared to controls of 1.03 (95% CI 0.85-1.24). There were no significant differences in COPD prevalence between patients with SpA and controls in men or women, in any of the age groups, or in analyses using stricter definitions of COPD. In this regional study including data from primary care, the prevalence of COPD was not increased in patients with SpA compared to the background population.

Alginate based biomaterials for hemostatic applications: Innovations and developments.

Development of the efficient hemostatic materials is an essential requirement for the management of hemorrhage caused by the emergency situations to avert most of the casualties. Such injuries require the use of external hemostats to facilitate the immediate blood clotting. A variety of commercially available hemostats are present in the market but most of them are associated with limitations such as exothermic reactions, low biocompatibility, and painful removal. Thus, fabrication of an ideal hemostatic composition for rapid blood clot formation, biocompatibility, and antimicrobial nature presents a real challenge to the bioengineers. Benefiting from their tunable fabrication properties, alginate-based hemostats are gaining importance due to their excellent biocompatibility, with >85 % cell viability, high absorption capacity exceeding 500 %, and cost-effectiveness. Furthermore, studies have estimated that wounds treated with sodium alginate exhibited a blood loss of 0.40 ± 0.05 mL, compared to the control group with 1.15 ± 0.13 mL, indicating its inherent hemostatic activity. This serves as a solid foundation for designing future hemostatic materials. Nevertheless, various combinations have been explored to further enhance the hemostatic potential of sodium alginate. In this review, we have discussed the possible role of alginate based composite hemostats incorporated with different hemostatic agents, such as inorganic materials, polymers, biological agents, herbal agents, and synthetic drugs. This article outlines the challenges which need to be addressed before the clinical trials and give an overview of the future research directions.

Benzopyrone, a privileged scaffold in drug discovery: An overview of FDA-approved drugs and clinical candidates.

Natural products have always served as an important source of drugs for treating various diseases. Among various privileged natural product scaffolds, the benzopyrone class of compounds has a substantial presence among biologically active compounds. One of the pioneering anticoagulant drugs, warfarin approved in 1954 bears a benzo-α-pyrone (coumarin) nucleus. The widely investigated psoriasis drugs, methoxsalen, and trioxsalen, also contain a benzo-α-pyrone nucleus. Benzo-γ-pyrone (chromone) containing drugs, cromoglic acid, and pranlukast were approved as treatments for asthma in 1982 and 2007, respectively. Numerous other small molecules with a benzopyrone core are under clinical investigation. The present review discusses the discovery, absorption, distribution, metabolism, excretion properties, and synthetic approaches for the Food and Drug Administration-approved and clinical-stage benzopyrone class of compounds. The role of the pyrone core in biological activity has also been discussed. The present review unravels the potential of benzopyrone core in medicinal chemistry and drug development.

Predictors at diagnosis for start of biologic disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis: a cohort study.

OBJECTIVES: To investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Consecutive patients (N=330) with early RA (symptom duration <12 months) diagnosed at Skåne University Hospital, Malmö/Lund, Sweden, from 2012 to 2016, were included. Data on demographics, education, comorbidities and treatment were obtained from national registers. OUTCOME: The relation between patient characteristics at diagnosis and time to first bDMARD/tsDMARD initiation was analysed using Cox regression models. As a secondary outcome, the relation between characteristics at diagnosis and b/tsDMARD initiation within 3 years was analysed using logistic regression. RESULTS: A total of 330 patients (mean age 59.2 years; SD 16.4) were included. During follow-up, 41% received a bDMARD (never preceded by a tsDMARD). Higher age at diagnosis was associated with a lower probability of starting bDMARD treatment (multivariable-adjusted HR 0.66 per SD; 95% CI 0.56 to 0.78). Anticitrullinated protein antibody (ACPA) positivity and higher tender joint count at diagnosis were also associated with subsequent bDMARD treatment initiation in multivariable analysis. A higher level of formal education and absence of comorbidities predicted start of a bDMARD in crude, but not in age-adjusted, analyses. CONCLUSIONS: Older patients with RA were less likely to start bDMARDs, whereas ACPA-positive patients, and those with extensive joint involvement at diagnosis, were more likely to receive early bDMARD treatment. The impact of age on the subsequent start of bDMARD therapy was not explained by level of education or comorbidities, suggesting that other aspects of age influence treatment decisions in early RA.