APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Pneumococcal vaccine uptake in patients with inflammatory arthritis: a single centre cohort study.

INTRODUCTION: Current guidelines recommend pneumococcal vaccination in individuals who are over the age of 65 or are immunosuppressed due to a disease or treatment. The objective of this study was to assess vaccine uptake rates in people with inflammatory arthritis for the pneumococcal, influenza and Covid-19 vaccines and factors determining uptake. METHODS: We conducted a retrospective single centre cohort study in the UK of individuals with rheumatoid arthritis, psoriatic arthritis and axial spondylarthritis between October and December 2023. Data were collected for age, gender, co-morbidities, immunosuppressive therapies, and dates of vaccines. Logistic regression was used to evaluate predictors of vaccine uptake, with adjustments for demographic and clinical factors. RESULTS: 906 individuals were identified. 46% were receiving treatment with csDMARD, 26% on biologic monotherapy, and 23% were on both biologic and csDMARDs. 316 individuals (35%) received a pneumococcal vaccine, lower than uptake for influenza (63%) and Covid-19 (87%) vaccines. Predictors of pneumococcal vaccine uptake included age, with older patients more likely to be vaccinated (odds ratio [OR] for age ≥ 65 years: 1.67, 95% CI 1.21-2.29). Those on biological therapy demonstrated higher likelihood of vaccination (OR for biologic therapy: 1.81, 95% CI 1.33-2.47). Additional Joint committee for immunisation and vaccination (JCVI) Green Book indicators also positively influenced vaccine uptake (OR: 1.67, 95% CI 1.19-2.33). CONCLUSION: Pneumococcal vaccine uptake in inflammatory rheumatic diseases is low, especially in younger patients and those not on biological therapy. The study highlights the need for a focused approach, distinct from strategies for other vaccines, to address this public health challenge.

Contract development and manufacturing organization selection: critical considerations that can make or break your cell and gene therapy development.

BACKGROUND AIMS: With the increase in cell and gene therapy (CGT) clinical trials in recent years has come a subsequent increase in the number of contract development and manufacturing organizations (CDMOs). Successful transition from development and early-phase clinical trials to commercialization of a CGT product often depends on selecting the best-suited CDMO. However, many CGT companies are small biotech companies that lack expertise in the field or do not have experience selecting and transferring a process to a CDMO. METHODS: Given the interest in this topic, a roundtable with CGT developers and CDMO members at the 2023 annual meeting of the International Society of Cell and Gene Therapy Paris discussed these critical aspects of product development, including technical expertise, risk sharing and timing of partnerships. RESULTS AND CONCLUSIONS: Here, we'll analyze the considerations discussed by the panel and elaborate on other factors crucial for CGT development.

Changes in seasonal respiratory viral infections among pediatric population around the COVID-19 pandemic; 2019-2023.

PURPOSE: This study aims to describe the prevalence and the fluctuations of respiratory viral infections among the pediatric population in a tertiary care center during 2019-2023, parallel with the COVID-19 pandemic, and the specific preventative measures applied in the region during this time. METHODS: In this observational study, we extracted all respiratory virus PCR tests collected from pediatric patients (< 15 years old) between January 2019 and March 2023. Data on the positivity rate and prevalence of 18 respiratory viruses were presented over the study period. RESULTS: The lowest rate for the studied respiratory viruses was observed in 2020/2021 (during the COVID-19 pandemic), followed by a gradual increase in positive cases in the 2021/2022 season. Timing (seasonality) was altered during 2022/2023 with an early circulation of respiratory viruses in May-June followed by an early start of the usual respiratory viruses' season in September, leading to prolonged respiratory virus activity. Most respiratory viruses were circulating at unprecedented levels during the 2022/2023 season, with rhinovirus/enterovirus being the most commonly detected virus in all seasons. Other viruses that had atypical activity after the COVID-19 pandemic were influenza A(H3) virus, adenovirus, and parainfluenza 3 virus. CONCLUSION: Our study demonstrates the extended influence of the COVID-19 pandemic and its associated community restriction measures on the timing and distribution of other respiratory viruses. Continuous monitoring of changes in the circulation of respiratory viruses is crucial for the success of related public health measures such as vaccination distributions and epidemic preparedness.

Longitudinal effects of affective distress on disease outcomes in rheumatoid arthritis: a meta-analysis and systematic review.

Patients with rheumatoid arthritis have higher rates of mental health conditions compared to the general population. It is believed that affective distress and rheumatoid arthritis have a bi-directional relationship. This review will examine the associations between affective distress and rheumatoid arthritis outcomes over time. Several disease outcomes are included covering disease activity, function, and disability to provide a broad picture of the various ways patients are impacted. A quality assessment was also conducted. There were 71 studies included in the review. Three measures (disease activity, disability, and mortality) had enough data to complete meta-analyses of odds ratios or hazard ratios. The outcomes included were disease activity, tender joint count, swollen joints, pain, physician global assessment, patient global assessment, physical disability, acute phase reactants, stiffness, fatigue, work disability, and mortality. Numerous measures were included for most of the outcomes due to the variability across studies of measures used. Patients with affective distress had lower rates of remission according to the DAS-28, greater disability, and higher mortality. All of the outcomes covered had studies with mixed results, but swollen joint count, tender joint count, patient global assessment, and physician global assessment had the strongest evidence that they were associated with mental health longitudinally. The relationships between affective distress and disease outcomes are complex and vary depending on the measures. Overall, the effects fade over time. It is important for clinicians to be aware of the differing manifestations of the relationship between affective distress and rheumatoid arthritis outcomes.

Molar root canal treatment performed by undergraduate dental students; an observational study of procedural errors and student perception.

BACKGROUND: Molar root canal treatment (RCT) is challenging and requires training and specific skills. Rotary instrumentation (RI) reduces the time needed for instrumentation but may increase the risk of certain procedural errors. The aims of this study were to evaluate the quality of molar RCTs provided by undergraduate students, to compare the prevalence of procedural errors following manual and RI, and to assess the students' self-perceived confidence to perform molar RCT without supervision and their preference for either manual or RI. METHODS: Molar RCTs performed by the final year students were evaluated radiographically according to predefined criteria (Appendix 1). The procedural errors, treatment details, and the students' self-perceived confidence to perform molar RCT and their preference for either manual or RI were recorded. Descriptive statistics were performed, and the Chi-squared test was used to detect any statistically significant differences. RESULTS: 60.4% of RCTs were insufficient. RI resulted in more sufficient treatments compared with MI (49% vs. 30.3% respectively. X2: 7.39, p = 0.007), required fewer visits to complete (2.9 vs. 4.6 respectively. X2: 67.23, p < 0.001) and was the preferred technique by 93.1% of students. The most common procedural errors were underextension of the root canal obturation (48.4%), insufficient obturation (45.5%), and improper coronal seal (35.2%) without a significant difference between the two techniques. 26.4% of the participating students reported that they did not feel confident to perform molar RCT without supervision. CONCLUSION: The quality of molar RCT provided by UG students was generally insufficient. RI partially improved the technical quality of RCT compared with MI. UG students need further endodontic training and experience before they can safely and confidently practise molar RCT.

Uncovering a neurological protein signature for severe COVID-19.

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has sparked a global pandemic with severe complications and high morbidity rate. Neurological symptoms in COVID-19 patients, and neurological sequelae post COVID-19 recovery have been extensively reported. Yet, neurological molecular signature and signaling pathways that are affected in the central nervous system (CNS) of COVID-19 severe patients remain still unknown and need to be identified. Plasma samples from 49 severe COVID-19 patients, 50 mild COVID-19 patients, and 40 healthy controls were subjected to Olink proteomics analysis of 184 CNS-enriched proteins. By using a multi-approach bioinformatics analysis, we identified a 34-neurological protein signature for COVID-19 severity and unveiled dysregulated neurological pathways in severe cases. Here, we identified a new neurological protein signature for severe COVID-19 that was validated in different independent cohorts using blood and postmortem brain samples and shown to correlate with neurological diseases and pharmacological drugs. This protein signature could potentially aid the development of prognostic and diagnostic tools for neurological complications in post-COVID-19 convalescent patients with long term neurological sequelae.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications.

OBJECTIVES: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate. METHODS: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data. CONCLUSIONS: JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons. PROSPERO REGISTRATION NUMBER: CRD42022362630.

COVID-19 admissions and mortality in patients with early inflammatory arthritis: results from a UK national cohort.

OBJECTIVE: To describe the risks and predictors of coronavirus disease 2019 (COVID-19) hospitalization and mortality among patients with early inflammatory arthritis (EIA), recruited to the National Early Inflammatory Arthritis Audit (NEIAA). METHODS: NEIAA is an observational cohort. We included adults with EIA from Feb 2020 to May 2021. Outcomes of interest were hospitalization and death due to COVID-19, using NHS Digital linkage. Cox proportional hazards were used to calculate hazard ratios for outcomes according to initial treatment strategy, with adjustment for confounders. RESULTS: From 14 127 patients with EIA, there were 143 hospitalizations and 47 deaths due to COVID-19, with incidence rates per 100 person-years of 0.93 (95% CI 0.79, 1.10) for hospitalization and 0.30 (95% CI 0.23, 0.40) for death. Increasing age, male gender, comorbidities and ex-smoking were associated with increased risk of worse COVID-19 outcomes. Higher baseline DAS28 was not associated with COVID-19 admissions [confounder adjusted hazard ratio (aHR) 1.10; 95% CI 0.97, 1.24] or mortality (aHR 1.11; 95% CI 0.90, 1.37). Seropositivity was not associated with either outcome. Higher symptom burden on patient-reported measures predicted worse COVID-19 outcomes. In unadjusted models, CS associated with COVID-19 death (HR 2.29; 95% CI 1.02, 5.13), and SSZ monotherapy associated with COVID-19 admission (HR 1.92; 95% CI 1.04, 3.56). In adjusted models, associations for CS and SSZ were not statistically significant. CONCLUSION: Patient characteristics have stronger associations with COVID-19 than the initial treatment strategy in patients with EIA. An important limitation is that we have not looked at treatment changes over time.

Implementing treat-to-target urate-lowering therapy during hospitalisations for gout flares.

OBJECTIVES: To evaluate a strategy designed to optimise care and increase uptake of urate-lowering therapy (ULT) during hospitalisations for gout flares. METHODS: We conducted a prospective cohort study to evaluate a strategy that combined optimal in-hospital gout management with a nurse-led, follow-up appointment, followed by handover to primary care. Outcomes, including ULT initiation, urate target attainment, and re-hospitalisation rates, were compared between patients hospitalised for flares in the 12 months post-implementation and a retrospective cohort of hospitalised patients from 12 months pre-implementation. RESULTS: 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months pre- and post-implementation. For patients with 6-month follow-up data available (n = 94 and n = 97, respectively), the proportion newly initiated on ULT increased from 49.2% pre-implementation to 92.3% post-implementation (age/sex-adjusted odds ratio (aOR) 11.5; 95% confidence interval (CI) 4.36-30.5; p < 0.001). After implementation, more patients achieved a serum urate ≤360 micromol/L within 6 months of discharge (10.6% pre-implementation vs. 26.8% post-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients re-hospitalised for flares was 14.9% pre-implementation vs. 9.3% post-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). CONCLUSION: Over 90% of patients were initiated on ULT after implementing a strategy to optimise hospital gout care. Despite increased initiation of ULT during flares, recurrent hospitalisations were not more frequent following implementation. Significant relative improvements in urate target attainment were observed post-implementation; however, for the majority of hospitalised gout patients to achieve urate targets, closer primary-secondary care integration is still needed.

Intra-clade Heterogeneity in Candida auris: Risk of Management.

Candida auris has emerged as a significant nosocomial fungal pathogen with a high risk of pathogenicity. Since the initial detection of C. auris in 2009, it gained lots of attention with a recent alert by the Centers for Disease Control and Prevention (CDC) due to its high infectivity and drug resistance. Several studies showed the capability of C. auris to secrete lytic enzymes, germinate, and form a biofilm that eventually results in interactions with the host cells, leading to serious infections. Other studies demonstrated a decrease in susceptibility of C. auris strains to available antifungals, which may be caused by mutations within the target genes, or the drug efflux pumps. However, the contribution of C. auris heterogeneity in pathogenicity and drug resistance is not well studied. Here, we shed light on the factors contributing to the development of heterogeneity in C. auris. These include phenotypic changes, biofilm formation, mechanisms of drug resistance, host invasion, mode of transmission, and expression of virulence factors. C. auris exhibits different phenotypes, particularly aggregative, and non-aggregative forms that play an important role in fungal heterogeneity, which significantly affects drug resistance and pathogenicity. Collectively, heterogeneity in C. auris significantly contributes to ineffective treatment, which in turn affects the fungal pathogenicity and drug resistance. Therefore, understanding the underlying reasons for C. auris heterogeneity and applying effective antifungal stewardship could play a major role in controlling this pathogen.

The role of trust in the implementation and uptake of COVID-19 response measures: a qualitative study of health professionals' experiences in Tanzania.

BACKGROUND: Even though trust is placed at the central point in ensuring proper functioning of the health systems, studies remain scant on how it affects both the implementation and uptake of COVID-19 response measures in low- and middle-income countries such as Tanzania. This study, therefore, explored the role of trust in the implementation and uptake of recommended COVID-19 response measures including vaccines from the perspective of health professionals in Tanzania. METHODS: This cross-sectional qualitative study was implemented in four of Tanzania's thirty-one regions. Qualitative data was collected through 26 in-depth interviews held with regional and district disease outbreak response teams, district cold chain co-ordinators and health facility in-charges. In addition, five focus group discussions and seven group interviews were conducted with healthcare workers from the lower-level health facilities. Thematic analysis was conducted and applied the trust constructs. RESULTS: Interpersonal trust and health system trust emerged as two major themes in the study. Interpersonal trust was reported to stem from lack of transparency that instigated fear, worries, and confusion regarding the implementation and uptake of the recommended response measures. The distrust was mainly between health professionals in health facilities and those assigned to isolation centres as well as between patients and community members. On the other hand, the health system trust was shaped by mixed feelings regarding COVID-19 vaccine national decisions, and conflicting messages from national officials, politicians and religious leaders on COVID-19 responses, safety, and effectiveness of the vaccines. Questions surrounding the short duration of clinical trials, indeterminate post-vaccination protection duration, impotence-linked beliefs, freemasonry notion and unclear vaccinated cards information are other reported contributory factors to mistrust in the health system. However, after a comprehensive health education and experience in COVID-19 vaccination administration most professionals affirmed the effectiveness of the vaccines in limiting infections and its severe consequences. CONCLUSION: Participants indicated limited trust at both interpersonal and health system levels aggravated by lack of transparency, unclear and conflicting messages on COVID-19 infections and response measures. Enforced transparency on pandemics alongside standardised messages from the reliable sources is crucial in enhancing trust in implementation and uptake of the recommended response measures.

Assessment of internal porosities for different placement techniques of bulk-fill resin-based composites: a micro-computed tomography study.

OBJECTIVES: The aim was to compare the porosity of different bulk-fill resin-based composites (RBCs) placement techniques to the conventional incremental technique using microcomputed tomography (µ-CT). MATERIAL AND METHODS: Occlusal cavities were prepared on extracted human molars, divided into five groups based on the placement technique (n = 10/group). Techniques examined were Monoblock-two-step (SureFil SDR flow + Ceram.X), Monoblock-two-step (Tetric EvoFlow Bulk-Fill + Tetric EvoCeram Bulk-Fill), Monoblock-one-step (Tetric EvoCeram Bulk-Fill), Monoblock with sonic activation (SonicFill2), and incremental technique (Filtek Z250). µ-CT scanning (SkyScan, Bruker, Belgium) assessed the number, volume of closed pores, and total porosity. Analysis of variance on ranks was used (Student-Newman-Keuls method and Mann-Whitney rank-sum test), to determine the significance of RBC viscosity and the sonication placement technique. The Spearman correlation method assessed the correlation between porosity characteristics (α = 0.05). RESULTS: The SonicFill2 presented a higher number of closed pores than the other groups (p < 0.05). The overall porosity within the restoration seemed greater in this order: Filtek Z250 > SonicFill2 > Tetric EvoFlow Bulk-Fill + Tetric EvoCeram Bulk-Fill > Tetric EvoCeram Bulk-Fill > SureFil SDR Flow + Ceram.X. Sonication was associated with increased number (p = 0.005) and volume (p = 0.036) of closed pores. A strong correlation was observed between the number and volume of closed pores (R2 = 0.549, p < 001). CONCLUSIONS: The monoblock technique with sonic activation showed significantly more internal porosity than the other placement techniques. Sonication during application contributed to the higher number and volume of closed pores than the passive bulk-fill application. CLINICAL RELEVANCE: Using bulk-fill materials enhances efficiency, yet void formation remains an issue, depending on viscosity and active/passive delivery of materials. Clinicians must familiarize themselves with effective placement techniques to reduce void formation and optimizing treatment outcomes.

Novel Schiff Base Derived from Amino Pyrene: Synthesis, Characterization, Crystal Structure Determination, and Anticancer Applications of the Ligand and Its Metal Complexes.

In this study, we report the cytotoxicity of a newly synthesized Schiff base HL ((E)-2-ethoxy-6((pyren-1-ylimino)methyl)phenol) and its derived metal complexes (Zn(II), Cu(II), Co(II), Cr(III), and Fe(III)) along with their structural characterizations by means of elemental analysis, magnetic moment, molar conductance, IR, UV-Vis, ESR, and mass spectrometry. The single X-ray diffraction of the HL shows that it exists in the phenol-imine form in its solid state. The NMR and IR data indicate that the bidentate binding of the Schiff base ligand with the metal center occurs during complexation through the azomethine nitrogen atom and the hydroxyl group oxygen atom of the 3-ethoxy salicylaldehyde. The electronic spectra and magnetic measurements indicate that the Co(II) complex has a tetrahedral geometry and that the Cr(III) and Fe(III) complexes have a distorted octahedral geometry. The ESR and electronic spectra suggest that the Cu(II) complex has a distorted tetrahedral geometry. The cytotoxic effects of the HL and all of the metal complexes were studied using human breast cancer (MCF-7) cells. The Cu(II) and Zn(II) complexes exhibited the highest activity against the tested cell line, with IC50 values of 5.66 and 12.74 µg/mL, respectively, and their activity was higher than that of the fluorouracil cancer drug against the MCF-7 cells (18.05 µg/mL).

Marginal Adaptation and Fracture Resistance of 3D Printed and CAD/CAM Milled Definitive Resin Matrix Ceramic Crowns.

AIM: To evaluate and compare the marginal adaptation and fracture resistance of resin matrix ceramic crowns fabricated using 3-dimensional (3D) printing and computer aided design/computer aided manufacturing (CAD/CAM) milling technology. MATERIALS AND METHODS: Thirty extracted human maxillary first premolars were prepared to receive crown restorations and grouped into 3 groups according to 3 different crown materials (n = 10): VE: teeth restored with milled Vita Enamic, CS: teeth restored with milled Cerasmart 270 and VSC: teeth restored with 3D-printed VarseoSmile Crown Plus. Marginal analysis was performed with the aid of a digital microscope at (230x) magnification, both before and after cementation with self-adhesive resin cement and analyzed with Image J analysis software. The fracture loads for each sample were then recorded using a universal testing machine in a single load-to-failure test up until the crowns failed. RESULTS: The lowest marginal gap values were recorded for VSC before (8.03 µm) and after (15.07 µm) cementation with significant difference compared to the other crown materials (p <0.05), while the differences between the milled groups were non-significant both before, (CS (11.35 µm) and VE (11.86 µm)), and after cementation, (CS (20.01 µm) and VE (21.08 µm)). In terms of fracture resistance, VE recorded significantly lower fracture load values (727.8 N) (p <0.05) than the crowns fabricated from CS (1213.8 N) and VSC (1181.5 N), which showed no statistically significant differences between each other. CONCLUSION: 3D printed definitive crowns outperformed CAD/CAM milled crowns in terms of marginal adaptation, along with comparable fracture resistance values.

Exploring LIPIDs for their potential to improves bioavailability of lipophilic drugs candidates: A review.

This review aims to provide a thorough examination of the benefits, challenges, and advancements in utilizing lipids for more effective drug delivery, ultimately contributing to the development of innovative approaches in pharmaceutical science. Lipophilic drugs, characterized by low aqueous solubility, present a formidable challenge in achieving effective delivery and absorption within the human body. To address this issue, one promising approach involves harnessing the potential of lipids. Lipids, in their diverse forms, serve as carriers, leveraging their unique capacity to enhance solubility, stability, and absorption of these challenging drugs. By facilitating improved intestinal solubility and selective lymphatic absorption of porously permeable drugs, lipids offer an array of possibilities for drug delivery. This versatile characteristic not only bolsters the pharmacological efficacy of drugs with low bioavailability but also contributes to enhanced therapeutic performance, ultimately reducing the required dose size and associated costs. This comprehensive review delves into the strategic formulation approaches that employ lipids as carriers to ameliorate drug solubility and bioavailability. Emphasis is placed on the critical considerations of lipid type, composition, and processing techniques when designing lipid-based formulations. This review meticulously examines the multifaceted challenges that come hand in hand with lipid-based formulations for lipophilic drugs, offering an insightful perspective on future trends. Regulatory considerations and the broad spectrum of potential applications are also thoughtfully discussed. In summary, this review presents a valuable repository of insights into the effective utilization of lipids as carriers, all aimed at elevating the bioavailability of lipophilic drugs.

Thymoquinone (TQ) Inhibits Inflammation and Migration of THP-1 Macrophages: Mechanistic Insights into the Prevention of Atherosclerosis Using In-Vitro and In-Silico Analysis.

Atherosclerosis is an inflammatory disease mediated by interferon (IFN-γ) in concert with cell adhesion molecules and chemokines. Thymoquinone (TQ), a flavonoid derived from Nigella sativa, is reported to have anti-inflammatory, antioxidant, and cardiovascular protective properties. We evaluated the effects of TQ on the key pathogenic stages of atherosclerosis, including cell viability, inflammatory gene expression, cell migration, and cholesterol efflux, on human THP-1 macrophages in-vitro. Moreover, in-silico analysis was performed to predict the molecular targets and signaling mechanisms. We demonstrated that TQ treatment had no effect on cell viability and decreased the expression of monocyte chemoattractant protein (MCP-1) and intercellular adhesion molecule (ICAM-1) in response to IFN-γ. In addition, we have also demonstrated that the THP-1 cell migration was inhibited by TQ in the absence or presence of MCP-1. Thymoquinone had no effect on cholesterol efflux from monocytes. In-silico analysis also identified several putative targets for TQ that are associated with inflammatory diseases and associated signaling pathways. Collectively, these results suggest that TQ has anti-inflammatory effects and may be a potential nutraceutical candidate for the prevention and treatment of atherosclerosis.

Worse outcomes linked to ethnicity for early inflammatory arthritis in England and Wales: a national cohort study.

OBJECTIVE: To assess variability in care quality and treatment outcomes across ethnicities in early inflammatory arthritis (EIA). METHODS: We conducted an observational cohort study in England and Wales from May 2018 to March 2020, including patients with a suspected/confirmed EIA diagnosis. Care quality was assessed against six metrics defined by national guidelines. Clinical outcomes were measured using DAS28. Outcomes between ethnic groups ('White', 'Black', 'Asian', 'Mixed', 'Other') were compared, and adjusted for confounders. RESULTS: A total of 35 807 eligible patients were analysed. Of those, 30 643 (85.6%) were White and 5164 (14.6%) were from ethnic minorities: 1035 (2.8%) Black; 2617 (7.3%) Asian; 238 (0.6%) Mixed; 1274 (3.5%) Other. In total, 12 955 patients had confirmed EIA, of whom 11 315 were White and 1640 were from ethnic minorities: 314 (2.4%) Black; 927 (7.1%) Asian; 70 (0.5%) Mixed; 329 (2.5%) Other. A total of 14 803 patients were assessed by rheumatology within three weeks, and 5642 started treatment within six weeks of referral. There were no significant differences by ethnicity. Ethnic minority patients had lower odds of disease remission at three months [adjusted odds ratio 0.79 (95% CI: 0.65, 0.96)] relative to White patients. Ethnic minorities were significantly less likely to receive initial treatment withMTX[0.68 (0.52, 0.90)] or with glucocorticoids [0.63 (0.49, 0.80)]. CONCLUSION: We demonstrate that some ethnic minorities are less likely to achieve disease remission in three months following EIA diagnosis. This is not explained by delays in referral or time to treatment. Our data highlight the need for investigation into the possible drivers of these inequitable outcomes and reappraisal of EIA management pathways.

Biodiversity of N-acyl homoserine lactonase (aiiA) gene from Bacillus subtilis.

Microorganisms rely on the benefit of using chemical signals called autoinducers (AIs) as a connection matter in term of population, this mechanism is known as quorum sensing (QS). Quorum sensing is responsible for formation of biofilm together with virulence in bacteria. The most known QS molecule is N-acyl homoserine lactones (AHLs). A lot of degrading enzymes including lactonases that open the AHL ring and acylases that breakdown its acyl side chain can degrade or inactivate AHL. Due to similarity in lactone ring structure among AHLs it is susceptible to most of lactonases. Bacillus species are among the most promising bacteria producing AHL-lactonase. The aim of the work is to identify and study the diversity of the AHL-Lactonase gene among different Bacillus subtilis as a promising Quorum Quenching (QQ) strategy to prevent bacterial infections and biofilm formation. The AHL-lactonase (aiiA) gene of 64 B. subtilis isolates was amplified and sequenced followed by multiple sequence alignment of the translated amino acid sequences, homology modeling and docking study. An expected PCR product of about 750 base pair was detected in 22 B. subtilis isolates, and the results revealed that the isolates' sequences showed identity ranged between 97.61% and 99.47% with those in the NCBI GenBank database with 100% query coverage and 0.0 E-value. In addition, the results revealed high level of identity between many aiiA gene sequences of our isolates as they were closely related to the same sequences to many sequences of the NCBI GenBank database. The alignment of the amino acid sequences from the 22 B. subtilis isolates indicated that 84.4% of the amino acid residues were conserved between the aligned sequences. Docking of the co-crystalized ligand to wildtype and H109Y mutated protein showed a significant reduction of docking score for the mutated protein. This result indicate that this mutation might affect recognition or at least kinetics of these enzymes and hence their roles in quorum-quenching.

Skeletal muscles and Covid-19: a systematic review of rhabdomyolysis and myositis in SARS-CoV-2 infection.

OBJECTIVES: Myalgia is a widely publicised feature of Covid-19, but severe muscle injury can occur. This systematic review summarises relevant evidence for skeletal muscle involvement in Covid-19. METHODS: A systematic search of OVID and Medline databases was conducted on 16/3/2021 and updated on 28/10/2021 to identify case reports or observational studies relating to skeletal muscle manifestations of Covid-19 (PROSPERO: CRD42020198637). Data from rhabdomyolysis case reports were combined and summary descriptive statistics calculated. Data relating to other manifestations were analysed for narrative review. RESULTS: 1920 articles were identified. From these, 61 case reports/series met inclusion criteria, covering 86 rhabdomyolysis cases. Median age of rhabdomyolysis patients was 50 years, (range 6-89). 49% had either hypertension, diabetes mellitus or obesity. 77% were male. Symptoms included myalgia (74%), fever (69%), cough (59%), dyspnoea (68%). Median peak CK was 15,783U/L. 28% required intravenous haemofiltration and 36% underwent mechanical ventilation. 62% recovered to discharge and 30% died. Dyspnoea, elevated CRP and need for intravenous haemofiltration increased risk of fatal outcome. Additional articles relating to skeletal muscular pathologies include 6 possible concomitant diagnoses or relapses of idiopathic inflammatory myopathies and 10 reports of viral-induced muscle injuries without rhabdomyolysis. Localised myositis and rhabdomyolysis with SARS-CoV-2 vaccination have been reported. CONCLUSIONS: Rhabdomyolysis is an infrequent but important complication of Covid-19. Increased mortality was associated with a high CRP, renal replacement therapy and dyspnoea. The idiopathic inflammatory myopathies (IIM) may have viral environmental triggers. However, to date the limited number of case reports do not confirm an association with Covid-19.