Policy, practice, and prediction: model-based approaches to evaluating N. gonorrhoeae antibiotic susceptibility test uptake in Australia.

BACKGROUND: Antimicrobial resistance (AMR) represents a significant threat to global health with Neisseria gonorrhoea emerging as a key pathogen of concern. In Australia, the Australian Gonococcal Surveillance Program (AGSP) plays a critical role in monitoring resistance patterns. However, antibiotic susceptibility test (AST) uptake - a crucial component for effective resistance surveillance - remains to be a limiting factor. The study aims to model the processes involved in generating AST tests for N. gonorrhoea isolates within the Australian healthcare system and assess the potential impact of systematic and policy-level changes. METHODS: Two models were developed. The first model was a mathematical stochastic health systems model (SHSM) and a Bayesian Belief Network (BBN) to simulate the clinician-patient dynamics influencing AST initiation. Key variables were identified through systematic literature review to inform the construction of both models. Scenario analyses were conducted with the modification of model parameters. RESULTS: The SHSM and BBN highlighted clinician education and the use of clinical support tools as effective strategies to improve AST. Scenario analysis further identified adherence to guidelines and changes in patient-level factors, such as persistence of symptoms and high-risk behaviours, as significant determinants. Both models supported the notion of mandated testing to achieve higher AST initiation rates but with considerations necessary regarding practicality, laboratory constraints, and culture failure rate. CONCLUSION: The study fundamentally demonstrates a novel approach to conceptualising the patient-clinician dynamic within AMR testing utilising a model-based approach. It suggests targeted interventions to educational, support tools, and legislative framework as feasible strategies to improve AST initiation rates. However, the research fundamentally highlights substantial research gaps in the underlying understanding of AMR.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Strengthening antimicrobial resistance surveillance systems: a scoping review.

BACKGROUND: Antimicrobial resistance (AMR) is an emerging global public health crisis. Surveillance is a fundamental component in the monitoring and evaluation of AMR mitigation endeavours. The primary aim of the scoping review is to identify successes, barriers, and gaps in implementing AMR surveillance systems and utilising data from them. METHODS: PubMed, Web of Science, SCOPUS, and EMBASE databases were searched systematically to identify literature pertaining to implementation, monitoring, and evaluation of AMR surveillance systems. A thematic analysis was conducted where themes within the literature were inductively grouped based on the described content. RESULTS: The systematic search yielded 639 journal articles for screening. Following deduplication and screening, 46 articles were determined to be appropriate for inclusion. Generally, most studies focused on human AMR surveillance (n = 38, 82.6%). Regionally, there was equal focus on low- and middle-income countries (n = 7, 15.2%) and trans-national contexts (n = 7, 14.5%). All included articles (n = 46, 100.0%) discussed barriers to either implementing or utilising AMR surveillance systems. From the scoping review, 6 themes emerged: capacity for surveillance, data infrastructure, policy, representativeness, stakeholder engagement, and sustainability. Data infrastructure was most frequently discussed as problematic in evaluation of surveillance systems (n = 36, 75.0%). The most frequent success to surveillance system implementation was stakeholder engagement (n = 30, 65.2%). CONCLUSIONS: Experiences of AMR surveillance systems are diverse across contexts. There is a distinct separation of experiences between systems with emerging surveillance systems and those with established systems. Surveillance systems require extensive refinement to become representative and meet surveillance objectives.

The association of varying treatment thresholds of mepolizumab on asthma exacerbations in adults.

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited.Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use.Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period.Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

Sensorimotor synchronization with visual, auditory, and tactile modalities.

While it is well known that humans are highly responsive to rhythm, the factors that influence our ability to synchronize remain unclear. In the current study, we examined how stimulus modality and rhythmic deviation, along with the synchronizer's level of musicality, impacted sensorimotor synchronization (SMS). Utilizing a finger-tapping task and three sensory modalities (visual, auditory, and tactile), we manipulated rhythmic deviation by varying the temporal position, intensity, and availability of cues across four deviation levels. Additionally, to determine our participants' musical familiarity and aptitude, we administered the Goldsmiths Musical Sophistication Index (Gold-MSI) questionnaire. We found that SMS to external rhythmic stimuli was significantly more precise for auditory and tactile than for visual sequences. Further, we found SMS consistency significantly decreased in all modalities with increased rhythmic deviation, suggesting rhythmic deviation directly relates to SMS difficulty. Moreover, a significant correlation was found between Gold-MSI scores and SMS consistency in the most rhythmically deviant level, such that the higher one's musical general sophistication score, the greater one's SMS ability. This held for all three modalities. Combined, these findings suggest that rhythmic synchronization performance is affected not only by the modality and rhythmic deviation of the stimuli but also by the musical general sophistication of the synchronizer.

Simu-dependent clearance of dying cells regulates macrophage function and inflammation resolution.

Macrophages encounter and clear apoptotic cells during normal development and homeostasis, including at numerous sites of pathology. Clearance of apoptotic cells has been intensively studied, but the effects of macrophage-apoptotic cell interactions on macrophage behaviour are poorly understood. Using Drosophila embryos, we have exploited the ease of manipulating cell death and apoptotic cell clearance in this model to identify that the loss of the apoptotic cell clearance receptor Six-microns-under (Simu) leads to perturbation of macrophage migration and inflammatory responses via pathological levels of apoptotic cells. Removal of apoptosis ameliorates these phenotypes, while acute induction of apoptosis phenocopies these defects and reveals that phagocytosis of apoptotic cells is not necessary for their anti-inflammatory action. Furthermore, Simu is necessary for clearance of necrotic debris and retention of macrophages at wounds. Thus, Simu is a general detector of damaged self and represents a novel molecular player regulating macrophages during resolution of inflammation.

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.

BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point. RESULTS: Across all studies, the treatment effect on 3-year total GFR slope (median R2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. CONCLUSIONS: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

Are macrophages the heroes or villains during cryptococcosis?

Cryptococcus infections represents a major healthcare burden, with over 200,000 cases globally a year and even with treatment, mortality remains as high as 80%. There is a clear need for new classes of treatment, especially with the global threat of antifungal resistance. Several groups are investigating the potential of immunotherapy - circumventing many of the issues with current treatments. Macrophages are a cell type known to be heavily associated with cryptococcal infection, from the innate immune response through to the later stage chronic adaptive response - making these an ideal target for manipulation. However, it is currently debated whether macrophage activity is positive or negative for host outcomes. Here, we discuss the current literature surrounding the role of macrophages during Cryptococcus infection, and makes cases for and against macrophage enhancement. Finally, we discuss which pressing questions in the field still remain that require answers in order to safely design an immunotherapeutic with high efficacy.

Kinetic Basis of Cis- and Trans-Allostery in GLUT1-Mediated Sugar Transport.

A growing body of evidence demonstrates that GLUT1-mediated erythrocyte sugar transport is more complex than widely assumed and that contemporary interpretations of emergent GLUT1 structural data are incompatible with the available transport and biochemical data. This study examines the kinetic basis of one such incompatibility-transport allostery-and in doing so suggests how the results of studies examining GLUT1 structure and function may be reconciled. Three types of allostery are observed in GLUT1-mediated, human erythrocyte sugar transport: (1) exofacial cis-allostery in which low concentrations of extracellular inhibitors stimulate sugar uptake while high concentrations inhibit transport; (2) endofacial cis-allostery in which low concentrations of intracellular inhibitors enhance cytochalasin B binding to GLUT1 while high concentrations inhibit binding, and (3) trans-allostery in which low concentrations of ligands acting at one cell surface stimulate ligand binding at or sugar transport from the other surface while high concentrations inhibit these processes. We consider several kinetic models to account for these phenomena. Our results show that an inhibitor can only stimulate then inhibit sugar uptake if (1) the transporter binds two or more molecules of inhibitor; (2) high-affinity binding to the first site stimulates transport, and (3) low-affinity binding to the second site inhibits transport. Reviewing the available structural, transport, and ligand binding data, we propose that exofacial cis-allostery results from cross-talk between multiple, co-existent ligand interaction sites present in the exofacial cavity of each GLUT1 protein, whereas trans-allostery and endofacial cis-allostery require ligand-induced subunit-subunit interactions.

Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec.

Proinsulin-transferrin fusion protein (ProINS-Tf) has been designed and successfully expressed from the mammalian HEK293 cells (HEK-ProINS-Tf). It was found that HEK-ProINS-Tf could be converted into an activated form in the liver. Furthermore, HEK-ProINS-Tf was demonstrated as an extra-long acting insulin analogue with liver-specific insulin action in streptozotocin (STZ)-induced type 1 diabetic mice. However, due to the low production yield from transfected HEK293 cells, there are other interesting features, including the oral bioavailability, which have not been fully explored and characterized. To improve the protein production yield, an alternative protein expression system, ExpressTec using transgenic rice (Oryza sativa L.), was used. The intact and active rice-derived ProINS-Tf (ExpressTec-ProINS-Tf) was successfully expressed from the transgenic rice expression system. Our results suggested that, although the insulin-like bioactivity of ExpressTec-ProINS-Tf was slightly lower in vitro, its potency of in vivo blood glucose control was considerably stronger than that of HEK-ProINS-Tf. The oral delivery studies in type 1 diabetic mice demonstrated a prolonged control of blood glucose to near-normal levels after oral administration of ExpressTec-ProINS-Tf. Results in this report suggest that ExpressTec-ProINS-Tf is a promising insulin analog with advantages including low cost, prolonged and liver targeting effects, and most importantly, oral bioactivity.

WZB117 (2-Fluoro-6-(m-hydroxybenzoyloxy) Phenyl m-Hydroxybenzoate) Inhibits GLUT1-mediated Sugar Transport by Binding Reversibly at the Exofacial Sugar Binding Site.

WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits passive sugar transport in human erythrocytes and cancer cell lines and, by limiting glycolysis, inhibits tumor growth in mice. This study explores how WZB117 inhibits the erythrocyte sugar transporter glucose transport protein 1 (GLUT1) and examines the transporter isoform specificity of inhibition. WZB117 reversibly and competitively inhibits erythrocyte 3-O-methylglucose (3MG) uptake with Ki(app) = 6 µm but is a noncompetitive inhibitor of sugar exit. Cytochalasin B (CB) is a reversible, noncompetitive inhibitor of 3MG uptake with Ki(app) = 0.3 µm but is a competitive inhibitor of sugar exit indicating that WZB117 and CB bind at exofacial and endofacial sugar binding sites, respectively. WZB117 inhibition of GLUTs expressed in HEK293 cells follows the order of potency: insulin-regulated GLUT4 ≫ GLUT1 ≈ neuronal GLUT3. This may explain WZB117-induced murine lipodystrophy. Molecular docking suggests the following. 1) The WZB117 binding envelopes of exofacial GLUT1 and GLUT4 conformers differ significantly. 2) GLUT1 and GLUT4 exofacial conformers present multiple, adjacent glucose binding sites that overlap with WZB117 binding envelopes. 3) The GLUT1 exofacial conformer lacks a CB binding site. 4) The inward GLUT1 conformer presents overlapping endofacial WZB117, d-glucose, and CB binding envelopes. Interrogating the GLUT1 mechanism using WZB117 reveals that subsaturating WZB117 and CB stimulate erythrocyte 3MG uptake. Extracellular WZB117 does not affect CB binding to GLUT1, but intracellular WZB117 inhibits CB binding. These findings are incompatible with the alternating conformer carrier for glucose transport but are consistent with either a multisubunit, allosteric transporter, or a transporter in which each subunit presents multiple, interacting ligand binding sites.

Enhanced Degradation of TCE on a Superfund Site Using Endophyte-Assisted Poplar Tree Phytoremediation.

Trichloroethylene (TCE) is a widespread environmental pollutant common in groundwater plumes associated with industrial manufacturing areas. We had previously isolated and characterized a natural bacterial endophyte, Enterobacter sp. strain PDN3, of poplar trees, that rapidly metabolizes TCE, releasing chloride ion. We now report findings from a successful three-year field trial of endophyte-assisted phytoremediation on the Middlefield-Ellis-Whisman Superfund Study Area TCE plume in the Silicon Valley of California. The inoculated poplar trees exhibited increased growth and reduced TCE phytotoxic effects with a 32% increase in trunk diameter compared to mock-inoculated control poplar trees. The inoculated trees excreted 50% more chloride ion into the rhizosphere, indicative of increased TCE metabolism in planta. Data from tree core analysis of the tree tissues provided further supporting evidence of the enhanced rate of degradation of the chlorinated solvents in the inoculated trees. Test well groundwater analyses demonstrated a marked decrease in concentration of TCE and its derivatives from the tree-associated groundwater plume. The concentration of TCE decreased from 300 µg/L upstream of the planted area to less than 5 µg/L downstream of the planted area. TCE derivatives were similarly removed with cis-1,2-dichloroethene decreasing from 160 µg/L to less than 5 µg/L and trans-1,2-dichloroethene decreasing from 3.1 µg/L to less than 0.5 µg/L downstream of the planted trees. 1,1-dichloroethene and vinyl chloride both decreased from 6.8 and 0.77 µg/L, respectively, to below the reporting limit of 0.5 µg/L providing strong evidence of the ability of the endophytic inoculated trees to effectively remove TCE from affected groundwater. The combination of native pollutant-degrading endophytic bacteria and fast-growing poplar tree systems offers a readily deployable, cost-effective approach for the degradation of TCE, and may help mitigate potential transfer up the food chain, volatilization to the atmosphere, as well as direct phytotoxic impacts to plants used in this type of phytoremediation.

Heading in football, long-term cognitive decline and dementia: evidence from screening retired professional footballers.

BACKGROUND: Heading impairs cognition in the short and medium-terms; however, little is known about the long-term consequences. This study aimed to investigate the hypothesis that chronic low-level head trauma is associated with persistent cognitive decline. METHODS: All members of Former Player Associations (FPAs) from four professional football clubs in the UK were contacted to participate in the study. Participants were required to complete a self-assessed test of cognition, the Test Your Memory questionnaire. Further information was collected from respondents in order to analyse the potential effect of a number of variables on cognition. RESULTS: 10 of 92 respondents (10.87%) screened positive for possible mild cognitive impairment (MCI) or dementia. There was no association between low-risk and high-risk playing positions (HR = 0.40, p = 0.456) or length of playing career (HR = 1.051 95% CI 0.879 to 1.257, p = 0.586) and a positive screening result. Age was a risk factor (HR = 1.137 per additional year, 95% CI 1.030 to 1.255, p < 0.05), although this was not significantly different from the population prevalence across age groups. CONCLUSIONS: These results suggest that once a player ends their playing career, their risk of harm falls in line with the population, suggesting either that changes are reversible or that heading may not be as harmful as commonly thought. Future longitudinal studies of large numbers of professional football players are needed to support the findings from this study.

The contribution of auditory imagery and visual rhythm perception to sensorimotor synchronization with external and imagined rhythm.

Sensorimotor synchronization (SMS) refers to the temporal coordination of an external stimulus with movement. Our previous work revealed that while SMS with visual flashing patterns was less consistent than with auditory or tactile patterns, it was still evident in a sample of nonmusicians. Although previous studies have speculated the potential role of auditory imagery, its contribution to visual SMS performance is not well quantified. Utilizing a synchronization-continuation finger-tapping task with a visual stimulus that included implied motion, we aimed to examine how participants' imagery ability, musicality, and rhythm perception affected SMS performance. We quantified participants' SMS consistency in synchronization (with visual cues) and continuation (without visual cues) phases. Participants also performed a perception task assessing their ability to detect temporal perturbations in the visual rhythm and completed musical ability and imagery questionnaires. Our linear regression model for SMS consistency included the trial phase, self-reported auditory imagery control and musicality, and visual rhythm perception as predictors. Significant effects of trial phase and auditory imagery scores on SMS consistency suggested that participants performed SMS more consistently while the guiding visual stimulus was present and that the higher one's self-reported auditory imagery ability, the better their SMS when continuing with unguided rhythm. One's visual rhythm perception accuracy significantly correlated with SMS consistency during the synchronization phase, and there was no correlation between rhythm perception and auditory imagery control. Overall, our results suggested relatively independent contributions of auditory imagery and visual rhythm perception to SMS with visual rhythm. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

DNA barcoding aids in generating a preliminary checklist of the lichens and allied fungi of Calvert Island, British Columbia: Results from the 2018 Hakai Terrestrial BioBlitz.

Background: Bioblitzes are a tool for the rapid appraisal of biodiversity and are particularly useful in remote and understudied regions and for understudied taxa. Lichens are an example of an often overlooked group, despite being widespread in virtually all terrestrial ecosystems and having many important ecological functions. New information: We report the lichens and allied fungi collected during the 2018 terrestrial bioblitz conducted on Calvert Island on the Central Coast of British Columbia, Canada. We identified 449 specimens belonging to 189 species in 85 genera, increasing the total number of species known from Calvert Island to 194, and generated Internal Transcribed Spacer (ITS) sequences for 215 specimens from 121 species. Bryoriafurcellata, Chaenothecopsislecanactidis and C.nigripunctata were collected for the first time in British Columbia. We also found Pseudocyphellariarainierensis, which is listed as Special Concern on the federal Species at Risk Act, and other rarely reported species in British Columbia including Opegraphasphaerophoricola, Protomicarealimosa, Raesaeneniahuuskonenii and Sareadifformis. We demonstrate that DNA barcoding improves the scope and accuracy of expert-led bioblitzes by facilitating the detection of cryptic species and allowing for consistent identification of chemically and morphologically overlapping taxa. Despite the spatial and temporal limitations of our study, the results highlight the value of intact forest ecosystems on the Central Coast of British Columbia for lichen biodiversity, education and conservation.

Smaller Differences in the Comparative Effectiveness of Biologics in Reducing Asthma-Related Hospitalizations Compared With Overall Exacerbations.

BACKGROUND: Evidence on the comparative effectiveness of respiratory biologics remains sparse. OBJECTIVE: We sought to evaluate the comparative effectiveness of omalizumab, mepolizumab, benralizumab, and dupilumab in a matched retrospective cohort of patients with asthma. METHODS: We identified patients with asthma aged ≥18 years who were incident users of these biologics between November 1, 2018, and June 30, 2023, in administrative claims data from the Food and Drug Administration's Sentinel System and Merative MarketScan Commercial Database. We compared asthma-related exacerbations and hospitalizations in the 12 months since biologic prescription in pairwise comparisons of propensity score-matched cohorts. Covariates used in matching included age, sex, allergic comorbidities, baseline asthma medications use, and the Charlson Comorbidity Index. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using negative binomial regression models. RESULTS: A total of 893 patients on mepolizumab, 1300 on benralizumab, 1170 on omalizumab, and 1863 on dupilumab were identified. The average age was 55 years, and two-thirds of the participants were female. At baseline, over 80% of these individuals had an active prescription for an inhaled corticosteroid. Almost half of patients on dupilumab had concomitant nasal polyposis compared with 6% to 13% of patients on the other biologics. Covariates were balanced after matching. In matched analyses, dupilumab was associated with the lowest incidence of exacerbations over the follow-up period (vs dupilumab): mepolizumab (IRR: 1.36; 95% CI: 1.12, 1.64), omalizumab (IRR: 1.33; 95% CI: 1.13, 1.58), benralizumab (IRR: 1.19; 95% CI: 1.00, 1.41). For exacerbations leading to hospitalizations, benralizumab and mepolizumab were associated with the lowest incidence of hospitalizations, and the greatest difference was between mepolizumab versus dupilumab (IRR: 0.76; 95% CI: 0.56, 1.03). CONCLUSIONS: Dupilumab was associated with the lowest incidence of overall exacerbations, and mepolizumab with the lowest incidence of asthma hospitalizations in this administrative claims-based cohort of individuals with asthma. Despite matching propensity scores, residual confounding, such as baseline eosinophil count, may explain some of these findings.

A comparison of two versus five epineural sutures to achieve successful polyethylene glycol (PEG) nerve fusion in a rat sciatic nerve repair model.

Background: We compared rates of successful polyethylene glycol (PEG) nerve fusion between two epineural suture repairs (2SR) and five epineural suture repairs (5SR) in a rat sciatic nerve transection neurorrhaphy model. We hypothesise that the two and five epineural neural suture repair groups will achieve a similar rate of PEG fusion. Methods: Twenty-five Lewis rats underwent bilateral sciatic nerve transection. Primary neurorrhaphy (PN) consisting of 2SR in one hind limb and 5SR in the contralateral hind limb was performed utilizing PEG fusion. Successful PEG fusion was confirmed by a distal muscle twitch after nerve stimulation proximal to the nerve fusion site. Sciatic nerve conduction velocity (SNCV) across the repair site and the force generated by tibialis anterior muscle (TAM) contraction were also compared between the 2SR and 5SR groups. Results: Success rates were 100% for the 2SR and the 5SR groups. No statistically significant differences in SNCV (P = 0.444) or isometric tetanic TAM contractile force (P = 0.820) were observed between 2SR and 5SR in the setting of PEG fusion. Conclusion: These findings demonstrate no significant difference in successful PEG fusion between the 2SR and 5SR groups. In addition, the findings demonstrate no statistically significant differences in SNCV or isometric tetanic TAM contractile force following sciatic nerve transection when performing a 2SR or 5SR PN in the setting of PEG fusion. Successful PEG fusion can be achieved acutely with either a two or five-epineural suture repair in a rat model.

Fibrin Glue Acutely Blocks Distal Muscle Contraction after Confirmed Polyethylene Glycol Nerve Fusion: An Animal Study.

Background: Polyethylene glycol (PEG) is a synthetic, biodegradable, and hyperosmotic material promising in the treatment of acute peripheral nerve injuries. Our team set out to investigate the impact of fibrin glue upon PEG fusion in a rat model. Methods: Eighteen rats underwent sciatic nerve transection and PEG fusion. Electrophysiologic testing was performed to measure nerve function and distal muscle twitch. Fibrin glue was applied and testing repeated. Due to preliminary findings, fibrin glue was applied to an uncut nerve in five rodents and testing was conducted before and after glue application. Mann-Whitney U tests were used to compare median values between outcome measures. A Shapiro-Wilk test was used to determine normality of data for each comparison, significance set at a P value less than 0.05. Results: PEG fusion was confirmed in 13 nerves with no significant change in amplitude (P = 0.054), latency (P = 0.114), or conduction velocity (P = 0.114). Stimulation of nerves following PEG fusion produced distal muscle contraction in 100% of nerves. Following application of fibrin glue, there was a significant reduction in latency (P = 0.023), amplitude (P < 0.001), and conduction velocity (P = 0.023). Stimulation of the nerve after application of fibrin glue did not produce distal muscle twitch. Five uncut nerves with fibrin glue application blocked distal muscle contraction following stimulation. Conclusions: Our data suggest that fibrin glue alters the nerve's function. The immediate confirmation of PEG fusion via distal muscle twitch is blocked with application fibrin glue in this experimental model. Survival and functional outcome studies are necessary to understand if this has implications on the long-term functional outcomes.

Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis.

BACKGROUND: Antitumor necrosis factor (anti-TNF) inhibitors are first-line treatment among patients with ulcerative colitis (UC). With time, patients tend to lose response or become intolerant, necessitating switching to small cell biologics such as tofacitinib or vedolizumab. In this real-world study of a large, geographically diverse US population of TNF-experienced patients with UC, we evaluated the effectiveness and safety of newly initiating treatment with tofacitinib vs vedolizumab. METHODS: We conducted a cohort study using secondary data from a large US insurer (Anthem, Inc.). Our cohort included patients with UC newly initiating treatment with tofacitinib or vedolizumab. Patients were required to have evidence of treatment with anti-TNF inhibitors in the 6 months prior to cohort entry. The primary outcome was treatment persistence >52 weeks. Additionally, we evaluated the following secondary outcomes as additional measures of effectiveness and safety: (1) all-cause hospitalization; (2) total abdominal colectomy; (3) hospitalization for infection; (4) hospitalization for malignancy; (5) hospitalization for cardiac events; and (6) hospitalization for thromboembolic events. We used fine stratification by propensity scores to control for confounding by demographics, clinical factors, and treatment history at baseline. RESULTS: Our primary cohort included 168 new users of tofacitinib and 568 new users of vedolizumab. Tofacitinib was associated with lower treatment persistence (adjusted risked ratio, 0.77; 95% CI, 0.60 -0.99). Differences in secondary measures of effectiveness or safety between tofacitinib initiators vs vedolizumab initiators were not statistically significant (all-cause hospitalization, adjusted hazard ratio, 1.23; 95% CI, 0.83-1.84; total abdominal colectomy, adjusted HR, 1.79; 95% CI, 0.93-3.44;and hospitalization for any infection, adjusted HR, 1.94; 95% CI, 0.83-4.52). DISCUSSION: Ulcerative colitis patients with prior anti-TNF experience initiating tofacitinib demonstrated lower treatment persistence compared with those initiating vedolizumab. This finding is in contrast to other recent studies suggesting superior effectiveness of tofacitinib. Ultimately, head-to-head randomized, controlled trials that focus on directly measured end points may be needed to best inform clinical practice.

Anti-TNF-experienced patients with UC initiating vedolizumab demonstrated higher treatment persistence compared with those initiating tofacitinib in this real-world evaluation of comparative effectiveness. Ultimately, head-to-head randomized trials that focus on directly measured end points are needed to best inform clinical practice.

Potent and long-lasting humoral and cellular immunity against varicella zoster virus induced by mRNA-LNP vaccine.

Varicella zoster virus (VZV) is a highly contagious human herpes virus responsible for causing chickenpox (varicella) and shingles (herpes zoster). Despite the approval of a highly effective vaccine, Shingrix®, the global incidence of herpes zoster is increasing and the economic burden to the health care system and society are substantial due to significant loss of productivity and health complications, particularly among elderly and immunocompromised individuals. This is primarily because access to the vaccines remains mostly limited to countries within developed economies, such as USA and Canada. Therefore, similarly effective vaccines against VZV that are more accessible to the rest-of-the-world are necessary. In this study, we aimed to evaluate immunogenicity and memory response induced by three mRNA-LNP-based vaccine candidates targeting VZV's surface glycoprotein E (gE). C57BL/6 mice were immunized with each candidate vaccine, and humoral and cellular immune responses were assessed. Our results demonstrate that the mRNA-LNP-based vaccine candidates elicited robust and durable humoral responses specific to the gE antigen. Notably, mice vaccinated with the mRNA-LNP vaccines exhibited significantly higher antigen-specific T-cell cytokine production compared to the group receiving Shingrix®, the current standard of care vaccine. Additionally, mRNA-LNP vaccines induced long-lasting memory response, as evidenced by detection of persistent gE-specific Long-Lived Plasma Cells (LLPCs) and memory T cells four months after final immunization. These findings underscore the potential of our mRNA-LNP-based vaccine candidates in generating potent immune responses against VZV, offering promising prospects for their clinical development as an effective prophylactic vaccine against herpes zoster.