A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis : First-in-human trial of ChAd63-KH

BACKGROUND: Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. METHODS: We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. FINDINGS: ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. CONCLUSION: The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. TRIAL REGISTRATION: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359)

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reseña de publicaciones

Reseña de publicacione

The role of religious leaders in promoting acceptance of vaccination within a minority group: a qualitative study

Contains fulltext : 117840.pdf (publisher's version ) (Open Access)BACKGROUND: Although childhood vaccination programs have been very successful, vaccination coverage in minority groups may be considerably lower than in the general population. In order to increase vaccination coverage in such minority groups involvement of faith-based organizations and religious leaders has been advocated. We assessed the role of religious leaders in promoting acceptance or refusal of vaccination within an orthodox Protestant minority group with low vaccination coverage in The Netherlands. METHODS: Semi-structured interviews were conducted with orthodox Protestant religious leaders from various denominations, who were selected via purposeful sampling. Transcripts of the interviews were thematically analyzed, and emerging concepts were assessed for consistency using the constant comparative method from grounded theory. RESULTS: Data saturation was reached after 12 interviews. Three subgroups of religious leaders stood out: those who fully accepted vaccination and did not address the subject, those who had religious objections to vaccination but focused on a deliberate choice, and those who had religious objections to vaccination and preached against vaccination. The various approaches of the religious leaders seemed to be determined by the acceptance of vaccination in their congregation as well as by their personal point of view. All religious leaders emphasized the importance of voluntary vaccination programs and religious exemptions from vaccination requirements. In case of an epidemic of a vaccine preventable disease, they would appreciate a dialogue with the authorities. However, they were not willing to promote vaccination on behalf of authorities. CONCLUSION: Religious leaders' attitudes towards vaccination vary from full acceptance to clear refusal. According to orthodox Protestant church order, local congregation members appoint their religious leaders themselves. Obviously they choose leaders whose views are compatible with the views of the congregation members. Moreover, the positions of orthodox Protestant religious leaders on vaccination will not change easily, as their objections to vaccination are rooted in religious doctrine and they owe their authority to their interpretation and application of this doctrine. Although the dialogue with religious leaders that is pursued by the Dutch government may be helpful in controlling epidemics by other means than vaccination, it is unlikely to increase vaccination coverage

Mood, cognition and EEG changes during interferon alpha (alpha-IFN) treatment for chronic hepatitis C.

Abstract: Background: This study is aim to investigate concurrent long-term psychiatric. cognitive and neurophysiological measure's of alpha-IFN neurotoxicity in the treatment of chronic viral hepatitis. Methods: Twenty patients with HCV hepatitis were enrolled while treated with alpha-IFN (3-6 MU for 6-12 months). Neurotoxicity was evaluated by psychiatric [Hamilton Depression Rating Scale (HAM-D), Hamilton Scale for Anxiety (HAM-A), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI-Y)], complete cognitive and neurophysiological assessments (EEG : spectral analysis, P300). Patients were assessed at baseline (t(0)), 2 (t(1)) and 6 months (t(2)) since the beginning of therapy. Results: Depression scores significantly increased (HAM-D: t(0)=4.4+/-2.6; t(1)=8.9+/-3.9, p<0.00; and t(2)=1.7+/-3.8, p<0.001). A concurrent increase was shown also for anxiety (HAM-A: t(0)=6.0+/-3.2; t(1)=9.6+/-4.5, p<0.005; and t(2)=9.1+/-4.5, p<0.005). Significant neurophysiological effects were also detected: increase of alpha power (p<0.05) in frontal derivations, reduction of the mean dominant frequency (p<0.005) and increase of theta power (p<0.05) in parietal derivations. In contrast, no significant cognitive changes occurred. Limitations: The study was performed on a relative small sample of patients mainly with observational intentions. Biological data (e.g. blood cytokines samples) are not available: they could have given useful information about biological mechanisms related to the alterations observed

Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation

Thi Phuong Thao Hoang,1 Philipp Schindler,2 Nikolaus Börner,3 Max Masthoff,2 Mirjam Gerwing,2 Philippa von Beauvais,2 Enrico N De Toni,4 Christian M Lange,4 Jonel Trebicka,5 Haluk Morgül,6 Max Seidensticker,1 Jens Ricke,1 Andreas Pascher,6 Markus Guba,3 Michael Ingrisch,1 Moritz Wildgruber,1,&ast; Osman Öcal1,&ast; 1Department of Radiology, University Hospital, LMU Munich, Munich, Germany; 2Clinic for Radiology, University Hospital Muenster, Muenster, Germany; 3Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany; 4Department for Internal Medicine II, University Hospital, LMU Munich, Munich, Germany; 5Department for Internal Medicine B, Universitätsklinikum Münster, Münster, Germany; 6Department of General, Visceral and Transplant Surgery, Universitätsklinikum Münster, Münster, Germany&ast;These authors contributed equally to this workCorrespondence: Osman Öcal, Department of Radiology, University Hospital – LMU Munich, Marchioninistrasse 15, D-81377, München, Germany, Email [email protected]: To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model.Patients and Methods: This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan–Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years.Results: The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively.Conclusion: Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.Keywords: hepatocellular carcinoma, transplantation, imaging, recurrenc