EBioMedicine最新文献

Background: Targeted preventive strategies in persons living with HIV (PLWH) require markers to predict visceral leishmaniasis (VL). We conducted a longitudinal study in a HIV-cohort in VL-endemic North-West Ethiopia to 1) describe the pattern of Leishmania markers preceding VL; 2) identify Leishmania markers predictive of VL; 3) develop a clinical management algorithm according to predicted VL risk levels.

Methods: The PreLeisH study followed 490 adult PLWH free of VL at enrolment for up to two years (2017-2021). Blood RT-PCR targeting Leishmania kDNA, Leishmania serology and Leishmania urine antigen test (KAtex) were performed every 3-6 months. We calculated the sensitivity/specificity of the Leishmania markers for predicting VL and developed an algorithm for distinct clinical management strategies, with VL risk categories defined based on VL history, CD4 count and Leishmania markers (rK39 RDT & RT-PCR).

Findings: At enrolment, 485 (99%) study participants were on antiretroviral treatment; 360/490 (73.5%) were male; the median baseline CD4 count was 392 (IQR 259-586) cells/μL; 135 (27.5%) had previous VL. Incident VL was diagnosed in 34 (6.9%), with 32 (94%) displaying positive Leishmania markers before VL. In those without VL history, baseline rK39 RDT had 60% sensitivity and 84% specificity to predict VL; in patients with previous VL, RT-PCR had 71% sensitivity and 95% specificity. The algorithm defined 442 (92.3%) individuals at low VL risk (routine follow-up), 31 (6.5%) as moderate risk (secondary prophylaxis) and six (1.2%) as high risk (early treatment).

Interpretation: Leishmania infection markers can predict VL risk in PLWH. Interventional studies targeting those at high risk are needed.

Funding: The PreLeisH study was supported by grants from the Department of Economy, Science and Innovation of the Flemish Government, Belgium (757013) and the Directorate-General for Development Cooperation and Humanitarian Aid (DGD), Belgium (BE-BCE_KBO-0410057701-prg2022-5-ET).

Background: Following mild traumatic brain injury (mTBI), elevated concentrations of brain-specific blood proteins glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) may be indicative of intracranial lesions normally detected by head CT scans. We sought to validate the performance of this combination of biomarkers at predetermined cutoff values with an automated immunoassay to predict which patients did not have intracranial lesions.

Methods: This prospective, observational study was conducted in France and Spain at 16 emergency departments. Adult patients with mTBI were eligible if they had a head CT scan and gave a 10-ml blood sample within 12 h of injury. GFAP and UCH-L1 serum concentrations were measured and analysed, in less than an hour time, according to predefined cutoff values of 22 pg/ml and 327 pg/ml, respectively. Serum concentrations of S100B protein were concomitantly determined in a subset of patients. The primary outcome measures were the sensitivity and negative predictive value (NPV) of the combined GFAP-UCH-L1 test to rule out intracranial lesions on head CT scans.

Clinicaltrials: gov (NCT04032509).

Findings: Between August 2019 and June 2021, 1508 patients were recruited, and 1438 were included in the main analysis. Median age was 69 years (IQR 44-83). Most patients (74%) presented 3 h after trauma. 179 (12.4%) patients were positive for intracranial lesions by CT. The sensitivity of the combined test was 98.3% (95% CI 95.0-99.7) and the specificity 24.9 (95% CI 22.6-27.4), with a NPV of 99.1% (95% CI 97.1-99.8). Three patients with a positive CT scan had negative biomarker test results. S100B had a sensitivity of 83.0% (95% CI 76.2-88.2) and a NPV of 94.2% (95% CI 91.6-96.0). Patients with higher biomarker values more frequently had poorer recovery at 3 months after injury.

Interpretation: Testing for GFAP and UCH-L1, using validated cutoffs obtained with a new, fast automated immunoassay platform, accurately predicted the absence of intracranial lesions on head CT following mTBI.

Funding: This study is co-funded by the European Institute of Innovation and Technology (EIT) Health, a body of the European Union (Grant nº19474). Biomarkers tests were funded by bioMérieux.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease characterized by vascular amyloid-β (Aβ) deposition. CAA is often seen in the brains of elderly individuals and in a majority of patients with Alzheimer's disease. The molecular pathways triggered by vascular Aβ, causing vessel wall breakdown and ultimately leading to intracerebral haemorrhage and cognitive decline, remain poorly understood. The occurrence of CAA-related inflammation (CAA-ri) and Amyloid-Related Imaging Abnormalities (ARIA) have sparked interest for a role of neuroinflammation in CAA pathogenesis. This review discusses prior studies of neuroinflammation in CAA and outlines potential future research directions targeting candidates such as matrix metalloproteinases, complement activation, microglial activation, reactive astrocytes and parenchymal border macrophages. Understanding the role of neuroinflammation in CAA pathogenesis could help identify new therapeutic strategies.

Background: We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies.

Methods: Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT + CVP). From 2006 rituximab was added to IFRT + CVP (IFRT + R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively).

Findings: Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR] = 0.60, 95% CI = 0.37-0.98, p = 0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR = 0.44, 95% CI = 0.16-1.18, p = 0.11, 10-year OS 95% vs. 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p = 0.045). PFS of IFRT + R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT + CVP) was superior (HR = 0.36, 95% CI = 0.13-0.82, p = 0.013). Amongst PET-staged patients, PFS differences between IFRT + R-CVP vs. IFRT were maintained (HR = 0.38, 95% CI = 0.16-0.89, p = 0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR = 0.45, 95% CI = 0.26-0.79, p = 0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p = 0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p = 0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease.

Interpretation: Adjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL.

Funding: Cancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation.

Background: BK polyomavirus (BKV) DNAaemia occurs in 10% of recipients of kidney transplants, contributing to premature allograft failure. Evidence suggests disease is donor derived. Hypothetically, recipient infection with a different BKV serotype increases risk due to poorer immunological control. Thus, understanding the composition and activity of the humoral anti-BKV responses in donor/recipient (D/R) pairs is critical.

Methods: Using 224 paired pre-transplant D/R samples, BKV VP1 genotype-specific pseudoviruses were employed to define the breadth of the antibody response against different serotypes (ELISA) and, to characterise specific neutralising activity (nAb) using the 50% inhibitory concentration (LogIC50). Mismatch (MM) ratios were calculated using the ratio of recipient ELISA or nAb reactive BKV serotypes relative to the number of donor reactive serotypes.

Findings: BKV DNAaemia was observed in 28/224 recipients of kidney transplants. These recipients had lower nAb titres against all the serotypes, with median logIC50 values of 1.19-2.91, compared to non-viraemic recipients' median logIC50 values of 2.13-3.30. nAb D/R MM ratios >0.67 associated with significantly higher risk of BKV viraemia, with an adjusted odds ratio of 5.12 (95% CI 2.07 to 13.04; p < 0.001). Notably, a mismatch against donor serotype Ic and II associated with adjusted odds ratios of 8.12 (95% CI 2.10 to 35.61; p = 0.002) and 4.52 (95% CI 1.19 to 19.23; p = 0.03) respectively. 21 recipients demonstrated broadly neutralising responses against all the serotypes, none of whom developed BKV DNAaemia post-transplant. In contrast, there was poor concordance with PsV-specific ELISA data that quantified the total antibody response against different serotypes.

Interpretation: BKV nAb mismatch predicts post-transplant BKV DNAaemia. Specific mismatches in nAb, rather than total seroreactivity, are key indicators of BKV risk post-transplant. This has the potential to risk-stratify individuals and improve clinical outcomes by influencing the frequency of monitoring and individualised tailoring of immunosuppression. Furthermore, detailed examination of individuals with broadly neutralising responses may provide future therapeutic strategies.

Funding: The research was funded by St. Peters Trust, Royal Free Hospital Charity and Wellcome Trust (grant numbers RFCG1718/05, SPT97 and 204870/Z/WT_/Wellcome Trust/United Kingdom).

Background: Ambient pollution and non-optimal temperature are major risk factors for respiratory health. However, the relationships between short-term exposure to these factors and bronchiectasis mortality remain unknown.

Methods: A nationwide, time-stratified case-crossover study across Mainland China was conducted from 2013 to 2019. Records of bronchiectasis deaths were extracted from the National Death Registration Reporting Information System. Daily concentrations of fine particulate matter (PM_2.5), coarse particulate matter (PM_2.5-10), nitrogen dioxide (NO₂), ozone (O₃), and daily temperature were obtained from high-resolution prediction models. We utilized conditional logistic regression model and distributed lag nonlinear model to explore the associations of these exposures with bronchiectasis mortality.

Findings: We included a total of 19,320 bronchiectasis deaths. Air pollutant was associated with bronchiectasis mortality within the first 3 days after exposure and the exposure-response relationships were almost linear. An interquartile range increase in PM_2.5, PM_2.5-10, and O₃ was associated with increments of 3.18%, 4.14%, and 4.36% in bronchiectasis mortality at lag 02 d, respectively. Additionally, lower temperature was associated with higher odds of bronchiectasis mortality. Compared to referent temperature (23.6 °C), the odds ratio for bronchiectasis mortality associated with extremely low temperature (P₁: -13.4 °C) was 1.54 (95% CI: 1.05, 2.25).

Interpretation: This national study provides compelling evidence, and highlights the necessity and importance of reducing air pollution exposures and keeping warm for susceptible populations.

Funding: National Natural Science Foundation of China (81925001; 82330070); Innovation Program of Shanghai Municipal Education Commission (202101070007-E00097); Program of Shanghai Municipal Science and Technology Commission (21DZ2201800); Program of Shanghai Shenkang Development Center (SHDC12023110); and Major Project of National Health Commission of China.

Force-sensing biophysical cues in microenvironment, including extracellular matrix performances, stretch-mediated mechanics, shear stress and flow-induced hemodynamics, have a significant influence in regulating vascular morphogenesis and cardiac remodeling by mechanotransduction. Once cells perceive these extracellular mechanical stimuli, Piezo activation promotes calcium influx by forming integrin-adhesion-coupling receptors. This induces robust contractility of cytoskeleton structures to further transmit biomechanical alternations into nuclei by regulating Hippo-Yes associated protein (YAP) signaling pathway between cytoplasmic and nuclear translocation. Although biomechanical stimuli are widely studied in cardiovascular diseases, the expression of force-sensing proteins in response to cardiovascular mechanotransduction has not been systematically concluded. Therefore, this review will summarize the force-sensing Piezo, cytoskeleton and YAP proteins to mediate extracellular mechanics, and also give the prominent emphasis on intrinsic connection of these mechanical proteins and cardiovascular mechanotransduction. Extensive insights into cardiovascular mechanics may provide some new strategies for cardiovascular clinical therapy.

Background: Despite successes in multiple sclerosis (MS) drug development, the effectiveness of animal studies in predicting successful bench-to-bedside translation is uncertain. Our goal was to identify predictors of successful animal-to-human translation for MS by systematically comparing animal studies of approved disease-modifying therapies (DMTs) with those that failed in clinical trials due to efficacy or safety concerns.

Methods: Systematic review of animal studies testing MS DMTs, identified from searches in PubMed and EMBASE. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved versus failed DMTs. Effect sizes and testing under diverse experimental conditions were assessed as potential predictors for successful translation.

Findings: We included 497 animal studies, covering 15 approved and 11 failed DMTs, tested in approximately 30'000 animals. DMTs were tested in a small repertoire of experimental parameters: about 86% of studies used experimental autoimmune encephalomyelitis (EAE), 80% used mice, and 76% used female animals. There was no association between animal study outcomes or testing DMTs under varied conditions (e.g., different laboratories or models) and successful approval. Surprisingly, 91% of animal studies were published after first-in-MS trial and 91% after official regulatory approval.

Interpretation: Our findings emphasize the complexity in carrying drugs from animals to clinical practice. Specific challenges include limited experimental methods in animal research and a disconnect between preclinical and clinical research. We advocate for efforts to streamline drug development for MS to improve animal research's relevance for patients.

Funding: NIH, Swiss National Science Foundation, Universities Federation for Animal Welfare.

Background: The impact of the infecting SARS-CoV-2 variant of concern (VOC) and the vaccination status was determined on the magnitude, breadth, and durability of the neutralizing antibody (nAb) profile in a longitudinal multicentre cohort study.

Methods: 173 vaccinated and 56 non-vaccinated individuals were enrolled after SARS-CoV-2 Alpha, Delta, or Omicron infection and visited four times within 6 months and nAbs were measured for D614G, Alpha, Delta, BA.1, BA.2, BA.5, BQ.1.1, XBB.1.5 and JN.1.

Findings: Magnitude-breadth-analysis showed enhanced neutralization capacity in vaccinated individuals against multiple VOCs. Longitudinal analysis revealed sustained neutralization magnitude-breadth after antigenically distant Delta or Omicron breakthrough infection (BTI), with triple-vaccinated individuals showing significantly elevated titres and improved breadth. Antigenic mapping and antibody landscaping revealed initial boosting of vaccine-induced WT-specific responses after BTI, a shift in neutralization towards infecting VOCs at peak responses and an immune imprinted bias towards dominating WT immunity in the long-term. Despite that bias, machine-learning models confirmed a sustained shift of the immune-profiles following BTI.

Interpretation: In summary, our longitudinal analysis revealed delayed and short lived nAb shifts towards the infecting VOC, but an immune imprinted bias towards long-term vaccine induced immunity after BTI.

Funding: This work was funded by the Bavarian State Ministry of Science and the Arts for the CoVaKo study and the ForCovid project. The funders had no influence on the study design, data analysis or data interpretation.