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The ability of Mycobacterium tuberculosis (Mtb) to adapt to its surrounding environment is critical for the bacterium to successfully colonize its host. Transcriptional changes are a vital mechanism by which Mtb responds to key environmental signals experienced, such as pH, chloride (Cl - ), nitric oxide (NO), and hypoxia. However, much remains unknown regarding how Mtb coordinates its response to the disparate signals seen during infection. Utilizing a transcription factor (TF) overexpression plasmid library in combination with a pH/Cl - -responsive luciferase reporter, we identified the essential TF, PrrA, part of the PrrAB two-component system, as a TF involved in modulation of Mtb response to pH and Cl - . Further studies revealed that PrrA also affected Mtb response to NO and hypoxia, with prrA overexpression dampening induction of NO and hypoxia-responsive genes. PrrA is phosphorylated not just by its cognate sensor histidine kinase PrrB, but also by serine/threonine protein kinases (STPKs) at a second distinct site. Strikingly, a STPK-phosphoablative PrrA variant was significantly dampened in its response to NO versus wild type Mtb, disrupted in its ability to adaptively enter a non-replicative state upon extended NO exposure, and attenuated for in vivo colonization. Together, our results reveal PrrA as an important regulator of Mtb response to multiple environmental signals, and uncover a critical role of STPK regulation of PrrA in its function.

Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H+) gradient across lysosome membranes to facilitate the breakdown of cellular waste products. Through the process of ageing, the body becomes deficient in CoQ10, resulting in several systemic manifestations. On a cellular level, one of the consequences of CoQ10 deficiency is apoptosis, which can be visualised in tissues of the central nervous system (CNS). Diseases affecting the retina and brain such as age-related macular degeneration (AMD), glaucoma, Alzheimer’s disease (AD) and Parkinson’s disease (PD) have shown defects in cellular biochemical reactions attributed to reduced levels of CoQ10. Through further research into the pathogenesis of such conditions, the effects of CoQ10 deficiency can be counteracted through supplementation, early detection and intervention.

Background Understanding public and patient attitudes to clinical research is paramount to successful recruitment. The COVID-19 pandemic has led to additional hurdles in achieving this. Our aim is to understand the current factors and attitudes towards clinical trial participation in order to assist in recruitment to clinical trials. Methods We conducted face-to-face interviews with patients in the outpatient department at a tertiary eye hospital facilitated by a 32-item questionnaire developed by the research team. Patient characteristics were correlated with their responses, in addition to qualitative thematic text analysis. Results A total of 53 patients were interviewed. Forty per cent indicated that they would be willing to participate in clinical research in the current climate. General motivating factors for involvement in research included personal gain, altruism and contribution to innovation. Factors limiting participation included concerns regarding own safety, inconvenience, accessibility and lack of benefit. 22.6% of participants felt that the COVID-19 pandemic has changed their outlook on research. These were categorised into positive (increased awareness of the importance and need for research, altruism) and negative (increased anxiety, need to minimise exposure to the hospital environment) influences. Conclusions Factors influencing patients’ decisions to participate in trials are similar to those observed prior to COVID-19 but with an increased focus on the environment the research is conducted in. The COVID-19 pandemic has had positive and negative impacts on patient attitudes towards research. Trial design, with a particular focus on setting and safety measures, in reassuring patients is increasingly important.

BackgroundProteinuria is the most common manifestation of lupus nephritis (LN) and is a mediator of progressive kidney damage. Early reductions in urine protein creatinine ratio (UPCR) have shown to be predictive of improved long-term outcomes in LN. However, recent studies with monoclonal antibody therapies have demonstrated a lack of efficacy in patients with high proteinuria (UPCR ≥2 to ≥3 mg/mg), potentially due to an increase in renal excretion of drug.[1]-[4] In a pooled analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies, the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids resulted in earlier and greater reductions in proteinuria across biopsy classes, races, and ethnicities.[5]ObjectivesTo further characterize the efficacy and safety of voclosporin in patients with high proteinuria, we have analyzed outcomes in various subpopulations of patients with UPCR ≥2 mg/mg using the pooled dataset.MethodsBoth studies enrolled patients with biopsy-proven LN (Class III, IV, or V ± III/IV) within 6 months (or up to 2 years in AURORA 1) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Patients were randomized to voclosporin (23.7 mg BID) or placebo and treated for up to one year (48 weeks [AURA-LV], 52 weeks [AURORA 1]); all patients received MMF and low-dose steroids. For this post-hoc analysis, complete renal response (CRR) rates were evaluated in patients with baseline UPCR ≥2 mg/mg. Complete renal response was defined as UPCR ≤0.5 mg/mg with stable renal function, low-dose steroids, and no rescue medication. Subgroup analyses were based on the following: sex, age, race, ethnicity, biopsy class, and estimated glomerular filtration rate [eGFR] at baseline. Adverse events (AEs) and mean eGFR levels over time were also assessed.ResultsOf the 268 and 266 patients included in the voclosporin and control arms of the pooled analysis, respectively, 217 and 215 patients had a baseline UPCR ≥2 mg/mg (mean [SD], 5.2 [3.4] vs. 4.6 [2.9] mg/mg, respectively). At one year, the change from baseline in least squares (LS) mean (SE) UPCR was -3.8 (0.1) mg/mg in the voclosporin arm compared to -3.1 (0.2) mg/mg in the control arm (difference vs. control, -0.7; p=0.0003). A significantly greater percentage of voclosporin-treated patients achieved CRR at one year compared to the control arm (41.0% vs. 21.9%; odds ratio [OR] 2.48, p<0.0001). CRR rates were numerically greater in voclosporin-treated patients in both sexes and across all ages, races, ethnicities, biopsy classes, and baseline eGFR levels assessed, with OR >1 (Figure 1). Across biopsy classes, the highest rates of CRR were observed in Class III patients treated with voclosporin (50% vs 16.1% in control, p=0.0126), followed by Class IV (44% vs. 23.8%, p=0.0019), Class V with III or IV lesions (37.7% vs. 17% p=0.0306), and Class V (31.3% vs. 28.6%, p=0.81). Similar rates of AEs were reported in both arms, and mean eGFR levels were similar and stable over one year of treatment (Figure 2).ConclusionConsistent with results from the overall pooled study population, patients with UPCR ≥2 mg/mg at baseline treated with voclosporin achieved significantly higher renal response rates than patients treated with MMF and low-dose steroids alone regardless of baseline demographics or clinical characteristics. This is clinically relevant given the lack of safe and effective therapies for patients with high proteinuria.References[1]Furie RA et al. Ann Rheum Dis. 2022;81:100-107.[2]Jayne D et al. Ann Rheum Dis. 2022;81(4):496-506.[3]Liu T et al. Lupus. Apr 2022;31(4):424-432.[4]Rovin BH et al. Kidney Int. Feb 2022;101(2):403-413.[5]Arriens C et al. Arthritis Care Res. Aug 30 2022.Acknowledgements:NIL.Disclosure of InterestsEmily Littlejohn Speakers bureau: Aurinia Pharmaceuticals Inc., Consultant of: GSK, Salem Almaani Consultant of: Chemocentryx, Aurinia Pharmaceuticals Inc., Kezar, Vanessa Birardi Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Ernie Yap Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Chris Collins Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc.

Background Postpartum haemorrhage (PPH) continues to stand as the primary cause of maternal morbidity and mortality post-delivery, with twin pregnancies carrying a heightened risk of PPH compared to singleton deliveries. Objectives To investigate the incidence of primary PPH among twin pregnancies and report on maternal and peripartum characteristics within this population. Methods A literature search was conducted using data from PubMed, EMBASE, Cochrane, Scopus, and Web of Science. The search aimed to identify studies concerning mothers with twin pregnancies and postpartum haemorrhage (PPH) from the inception of each respective database to June 8th, 2023. Pooled means and proportions were analyzed using the generic inverse variance method. This review was registered prospectively with PROSPERO (CRD42023427192). Results A total of 21 studies involving 23,330 twin pregnant patients were included. Incidence of PPH for vaginal delivery and Caesarean delivery (CS) was found to be 10.9% (95% CI: -0.017, 0.235, I 2  = 96%) and 27.0% (95% CI: 0.180, 0.359, I 2  = 99%) respectively. In vitro fertilization (IVF) was the most common conception method at 62.0% (95% CI: 0.448, 0.792, I 2  = 100%) with 81.1% (95% CI: 0.708, 0.915, I 2  = 100%) of twins being dichorionic diamniotic. Conclusion This meta-analysis demonstrated more than one in ten vaginal deliveries and over one in four cesarean sections result in PPH for twin pregnancies. IVF is the predominant method of conception in this patient group and seems to contribute to subsequent PPH risk in specific mothers. While preliminary, these findings underscore the necessity for further well-designed and high-quality studies to validate these results.

Purpose Transcatheter arterial embolization (TAE) is increasingly utilized in the management of renal angiomyolipomas (AML). However, the growth in its application has not been matched by a proportional increase in the level of evidence validating its safety and efficacy. This meta-analysis aims to evaluate TAE in managing renal AMLs by examining the effects of tumour size reduction and technical success. Methods A literature search of several databases was conducted from inception to July 2023. Eligible studies reported adult patients (≥ 18 years old) who underwent TAE for renal AML. The pooled proportions were analyzed using a random-effects model. This review was registered in PROSPERO (CRD42023441331). Results A total of 32 studies comprising 1087 patients were included. The average preoperative tumour size across renal AMLs was 8.79 cm (95% CI: 7.64, 9.93; I 2  = 97%) and the post-operative tumour size was 6.47 cm (95% CI: 5.44, 7.50; I 2  = 98%). The mean decrease in tumour size was 1.85 cm (95% CI: 1.69, 2.00; I 2  = 23%), whereas the mean reduction in tumour size percentage was 43.30% (95% CI: 34.30, 52.30; I 2  = 98%). The technical success rate from 1059 embolizations was 95.70% (95% CI: 0.94, 0.97; I 2  = 44%), with 65 procedural failures reported. Conclusion This meta-analysis provides insights into the efficacy of TAE for renal AMLs, emphasizing notable tumour size reduction and a high technical success rate for selected patients. Despite identified biases, the findings support TAE as a valuable intervention, warranting further research to refine safety profiles and optimize patient outcomes.

PURPOSE: To compare measurements of corneal epithelial thickness using optical coherence tomography (OCT) and very high-frequency digital ultrasound (VHFDU). METHODS: Retrospective analysis of 189 virgin corneas and 175 post-laser refractive surgery (LRS) corneas that had corneal epithelial thickness measurement with RTVue Fourier-domain OCT (Optovue, Inc., Fremont, CA) (tear film included) and Artemis VHFDU (ArcScan Inc., Morrison, CO) (tear film excluded). Averages were calculated for the central 2-mm diameter zone and for two further concentric annuli of 1.5- and 0.5-mm width, each divided into eight sectors. Agreement was analyzed by mean difference (OCT – VHFDU), 95% limits of agreement (LoA) (1.96 standard deviation of the difference), and Bland–Altman analysis. RESULTS: In virgin epithelium, mean central thickness was 53.4 ± 3.20 In virgin epithelium, mean central thickness was 53.4 ± 3.20 µ m (range: 46 to 62 µ m) with OCT and 54.1 ± 2.96 µ m (range: 48 to 61 µ m) with VHFDU; OCT measured thinnest in 70% with a mean difference of −0.71 µ m (95% LoA of ±3.94 µ m, P < .001). In post-LRS epithelium, mean central thickness was 57.9 ± 6.08 µ m (range: 42 to 77 µ m) with OCT and 60.5 ± 6.47 µ m (range: 42 to 79 µ m) with VHFDU; OCT measured thinnest in 88%, with a mean difference of −2.48 µ m (95% LoA of ±5.33 µ m, P < .001). A larger difference between methods was more common with thicker epithelium. CONCLUSIONS: Corneal epithelial thickness measurements using OCT were found to be slightly thinner than for VHFDU. In contrast to VHFDU, OCT measurement includes the tear film, so the true difference is probably approximately 4 Corneal epithelial thickness measurements using OCT were found to be slightly thinner than for VHFDU. In contrast to VHFDU, OCT measurement includes the tear film, so the true difference is probably approximately 4 µ m more than reported. The difference was greatest inferiorly and higher for post-LRS eyes and in thicker epithelium. [[ J Refract Surg. 2015;31(7):438–445.]

The prevalence of anemia and its impact on frailty and physical function amongst the multiethnic older populations in the Southeast Asian (SEA) countries are often not well studied. Singapore, a nation comprised of multiethnic communities, is one of the most rapidly aging population globally. We aim to evaluate the prevalence of anemia and its impact on frailty, and physical function in Healthy Older People Everyday (HOPE)- an epidemiologic population-based study on community-dwelling older adults in Singapore. Cross-sectional study. Community. 480 adults ≥ 65 years old. Data were collected from interviewers-administered questionnaires on socio-demographics, FRAIL scale, Mini-Mental State Examination, EQ-5D, Barthel Index, and Lawton index. Hemoglobin concentration and physical assessments, including anthropometry, grip strength, timed up-and-go (TUG) were measured. The overall prevalence of anemia was 15.2% (73 out of 480). The Indian ethnic group had the highest prevalence of anemia (32%, OR=3.02; 95%CI= 1.23–7.41) with the lowest hemoglobin concentration compared to the overall population (13.0±1.3g/L and 13.5±1.4g/L, p=0.02). Hemoglobin levels and anemia were significantly associated with frailty (OR=2.28; 95% CI=1.02–5.10), low grip strength (OR=1.79; 95% CI=1.01–3.03), ≥ one IADL impairment (OR=2.35; 95% CI=1.39–3.97). Each 1 g/dL increase in hemoglobin was associated with a 6% decrease in frailty odds after adjusting for potential covariates (OR = 0.94, 95% CI: 0.90–0.99). There was a significant difference in the mean TUG between the non-anemic (11.0±3.4 seconds) and anemic (12.3±6.0 seconds, p=0.01) counterparts, but no difference in the number of falls. In our multiethnic Asian population, anemia was adversely associated with frailty, decreased muscle strength, and IADL impairment. Health policies on anemia screening should be employed to avoid or potentially delay or reverse these adverse outcomes associated with anemia. Recognition, evaluation, and treatment of anemia amongst this vulnerable population is warranted.

Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.

Background:Lupus nephritis (LN) is characterized by proteinuria, which is not only a marker of active kidney inflammation, but also a driver of progressive kidney injury. Early reduction in proteinuria following treatment initiation has been shown to be a predictor of long-term kidney survival and overall mortality. The AURA-LV and AURORA 1 clinical trials have shown that voclosporin-based triple therapy with lower-dose MMF, and low-dose glucocorticoids (GCs) led to early and significant reductions in proteinuria with an acceptable safety profile. However, dual-immunosuppressive regimens containing high-dose glucocorticoids (GCs) and higher doses (>2 g/day) of mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) are still frequently used for the management of active LN in the belief that they may be more efficacious and safer.Objectives:To compare the safety and efficacy of a voclosporin-based, triple immunosuppressive regimen to a dual-immunosuppressive regimen for the treatment of active LN, we analyzed outcomes in propensity-matched participants from the ALMS, AURA-LV, and AURORA 1 studies. We hypothesized that a voclosporin-based, triple therapy approach would reduce exposure to the toxicities associated with higher doses of GCs, MMF, and IVC, resulting in an improved safety profile without compromising efficacy.Methods:All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months.Results:Propensity matching identified 179 participant pairs with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants in ALMS over the 6-month period. More participants in AURA-LV and AURORA 1 reported hypertension and anemia. Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; a greater number of events of GFR decreased were reported by AURA-LV/AURORA 1 participants. The incidence of serious AEs was similar across groups. UPCR ≤0.5 mg/mg was achieved by 52% of voclosporin-treated participants compared to 41.1% of IVC- or MMF-treated participants of ALMS; the median time to this endpoint for the voclosporin group was 142 days; a median time was not determinable for ALMS participants as less than 50% achieved the endpoint within the study period (hazard ratio [HR] 1.41; 95% confidence interval [CI] 1.03, 1.94; p=0.0324; Table 1, Figure 1). More voclosporin-treated participants achieved a 50% reduction in UPCR from baseline at any point during the study; this endpoint was met significantly earlier by voclosporin-treated patients as well (29 vs. 84 days; HR 1.88, 95% CI 1.48, 2.39; p<0.0001).Conclusion:Participants treated with voclosporin in combination with low-dose GCs and MMF 2g/day demonstrated an improved safety profile and earlier reductions in proteinuria compared to participants treated with high-dose GCs and MMF up to 3 g/day or IVC. These findings support the recommendation that a voclosporin-based, triple-immunosuppressive regimen should be considered as an initial therapy in patients with active LN.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Anca Askanase Consultant for Aurinia Pharmaceuticals Inc., AstraZeneca, GSK plc., Eli Lilly, Kenneth C. Kalunian: None declared, Maria Dall’Era Consultant for Annexon Biosciences, AstraZeneca, Aurinia Pharmaceuticals Inc., Biogen, GSK plc., and Pfizer, Grant/research support from Annexon Biosciences, GSK plc., Neil Solomons Shareholder of Aurinia Pharmaceuticals Inc., Former employee of Aurinia Pharmaceuticals Inc., Lucy Hodge Shareholder of Aurinia Pharmaceuticals, Inc., Employee of Aurinia Pharmaceuticals, Inc., Matt Truman Consultant for Aurinia Pharmaceuticals, Inc., Ernie Yap Shareholder of Aurinia Pharmaceuticals Inc., Employee of Aurinia Pharmaceuticals Inc.