FORMULATION AND EVALUATION OF ANTIMICROBIAL GELS FOR THE TREATMENT OF PARONYCHIA

Objective: The aim of the study was to design and develop a gel based drug delivery system containing combinational drugs (ketoconazole, neomycin sulphate and diclofenac) for the effective treatment of Paronychia.Methods: The drugs used are ketoconazole, neomycin sulphate and diclofenac. The first two drugs provide an antifungal and antibacterial action and the last drug with a pain relieving effect. Two formulations of gels F1 and F2 were prepared using polymers like carbopol 934 and xanthan gum respectively. The amounts of drugs and other ingredients were kept as constant in both formulations. The prepared formulations were then evaluated by visual examination, pH, drug content, spredability, extrudability, drug release study, in vitro antibacterial study, in vitro antifungal study, stability studies and in vivo antibacterial study.Results: The obtained results were analyzed and compared. All the test results were within the accepted limit. The physicochemical properties of the gels were assessed and it was found that the two formulations have enough gel consistency with good spreadability and extrudability. The drug content and drug release studies of the prepared gels were done and the results showed that the all the three drugs were properly loaded into the gel system, with good drug release profile. The antimicrobial activities of the formulated gels were proved by both in vitro antifungal and antibacterial studies. The in vivo antibacterial studies revealed a significant reduction in bacterial count in wistar rats treated with prepared gel when compared with standard drug solution. From among all the developed formulations, F1 formulation with carbopol 934 has got a slight superior property when compared with formulation F2 xanthan gum as gelling agent.Conclusion: On the basis of the evaluation studies it was concluded that the drugs (ketoconazole, neomycin sulphate and diclofenac) were successfully incorporated into the different topical gel preparations with good physicochemical properties and antimicrobial activity. Therefore, it was concluded that our formulae could be very promising topical alternative for the treatment of Paronychia

Loss of LEUCINE CARBOXYL METHYLTRANSFERASE 1 interferes with metal homeostasis in Arabidopsis and enhances susceptibility to environmental stresses

The biochemical function of LEUCINE CARBOXYL METHYLTRANSFERASE 1 (LCMT1) is to transfer a methyl group from the methyl donor S-adenosylmethionine (SAM) to the catalytic subunits of PROTEIN PHOSPHATASE 2A (PP2Ac), PP4 and PP6. This post-translational modification by LCMT1 is found throughout eukaryotes from yeast to animals and plants, indicating that its function is essential. However, Arabidopsis with knocked out LCMT1 still grows and develops almost normally, at least under optimal growth conditions. We therefore proposed that the presence of LCMT1 would be important under non-optimal growth conditions and favoured plant survival during evolution. To shed light on the physiological functions of plant LCMT1, phenotypes of the lcmt1 mutant and wild type Arabidopsis were compared under various conditions including exposure to heavy metals, variable chelator concentrations, and increased temperature. The lcmt1 mutant was found to be more susceptible to these environmental changes than wild type and resulted in poor growth of seedlings and rosette stage plants. Element analysis of rosette stage plants mainly showed a difference between the lcmt1 mutant and wild type regarding concentrations of sodium and boron, two-fold up or halved, respectively. In both lcmt1 and wild type, lack of EDTA in the growth medium resulted in enhanced concentration of copper, manganese, zinc and sulphur, and especially lcmt1 growth was hampered by these conditions. The altered phenotype in response to stress, the element and mRNA transcript analysis substantiate that LCMT1 has an important role in metal homeostasis and show that functional LCMT1 is necessary to prevent damages from heat, heavy metals or lack of chelator.publishedVersio

The BCD Triage Sieve outperforms all existing major incident triage tools:comparative analysis using the UK national trauma registry population

BACKGROUND: Natural disasters, conflict, and terrorism are major global causes of death and disability. Central to the healthcare response is triage, vital to ensure the right care is provided to the right patient at the right time. The ideal triage tool has high sensitivity for the highest priority (P1) patients with acceptably low over-triage. This study compared the performance of major incident triage tools in predicting P1 casualty status in adults in the prospective UK Trauma Audit and Research Network (TARN) registry. METHODS: TARN patients aged 16+ years (January 2008-December 2017) were included. Ten existing triage tools were applied using patients’ first recorded pre-hospital physiology. Patients were subsequently assigned triage categories (P1, P2, P3, Expectant or Dead) based on pre-defined, intervention-based criteria. Tool performance was assessed by comparing tool-predicted and intervention-based priority status. FINDINGS: 195,709 patients were included; mortality was 7·0% (n=13,601); median Injury Severity Score (ISS) was 9 (IQR 9–17); 97·1% sustained blunt injuries. 22,144 (11·3%) patients fulfilled intervention-based criteria for P1 status, exhibiting higher mortality (12·8% vs. 5·0%, p<0.001), increased intensive care requirement (52·4% vs 5·0%, p<0.001), and more severe injuries (median ISS 21 vs 9, p<0.001) compared with P2 patients. In 16–64 year olds, the highest performing tool was the Battlefield Casualty Drills (BCD) Triage Sieve (Prediction of P1 status: 70·4% sensitivity, over-triage 70·9%, area under the receiver operating curve (AUC) 0·068 [95%CI 0·676–0·684]). The UK National Ambulance Resilience Unit (NARU) Triage Sieve had sensitivity of 44·9%; over-triage 56·4%; AUC 0·666 (95%CI 0·662–0·670). All tools performed poorly amongst the elderly (65+ years). INTERPRETATION: The BCD Triage Sieve performed best in this nationally representative population; we recommend it supersede the NARU Triage Sieve as the UK primary major incident triage tool. Validated triage category definitions are recommended for appraising future major incidents. FUNDING: This study is funded by the National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre. GVG also acknowledges support from the MRC Heath Data Research UK (HDRUK/CFC/01). The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care, or the Ministry of Defence

Host Transcriptomics as a Tool to Identify Diagnostic and Mechanistic Immune Signatures of Tuberculosis

Tuberculosis (TB) is a major infectious disease worldwide, and is associated with several challenges for control and eradication. First, more accurate diagnostic tools that better represent the spectrum of infection states are required; in particular, identify the latent TB infected individuals with high risk of developing active TB. Second, we need to better understand, from a mechanistic point of view, why the immune system is unsuccessful in some cases for control and elimination of the pathogen. Host transcriptomics is a powerful approach to identify both diagnostic and mechanistic immune signatures of diseases. We have recently reported that optimal study design for these two purposes should be guided by different sets of criteria. Here, based on already published transcriptomics signatures of tuberculosis, we further develop these guidelines and identify additional factors to consider for obtaining diagnostic vs. mechanistic signatures in terms of cohorts, samples, data generation and analysis. Diagnostic studies should aim to identify small disease signatures with high discriminatory power across all affected populations, and against similar pathologies to TB. Specific focus should be made on improving the diagnosis of infected individuals at risk of developing active disease. Conversely, mechanistic studies should focus on tissues biopsies, immune relevant cell subsets, state of the art transcriptomic techniques and bioinformatics tools to understand the biological meaning of identified gene signatures that could facilitate therapeutic interventions. Finally, investigators should ensure their data are made publicly available along with complete annotations to facilitate metadata and cross-study analyses

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Antifungal activity of alexidine dihydrochloride in a novel diabetic mouse model of dermatophytosis

Dermatophytosis is one of the most prevalent fungal infections and a major public health problem worldwide. Recent years have seen a change in the epidemiological patterns of infecting fungi, corresponding to an alarming rise in the prevalence of drug-recalcitrant dermatophyte infections. In patients with diabetes mellitus, dermatophytosis is more severe and recurrent. The potency of promising new antifungal drugs in the pipeline must be expanded to include dermatophytosis. To facilitate this effort, we established a clinically pertinent mouse model of dermatophyte infections, in which diabetic mice were infected with Trichophyton mentagrophytes on abraded skin. The diabetic mouse model was optimized as a simple and robust system for simulating dermatophytoses in diabetic patients. The outcome of infection was measured using clinical and mycological parameters. Infected mice with fungal lesions were treated with oral and topical formulations of terbinafine or topical administration of the FDA-approved and repurposed pan-antifungal drug alexidine dihydrochloride (AXD). In this model, AXD was found to be highly effective, with outcomes comparable to those of the standard of care drug terbinafine. Copyright © 2022 Nabeela, Date, Ibrahim and Uppuluri.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]