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The Tarantula Nebula in the Large Magellanic Cloud is known for its high star formation activity. At its center lies the young massive star cluster R136, providing a significant amount of the energy that makes the nebula shine so brightly at many wavelengths. Recently, young massive star clusters have been suggested to also efficiently produce very high-energy cosmic rays, potentially beyond PeV energies. Here, we report the detection of very-high-energy γ -ray emission from the direction of R136 with the High Energy Stereoscopic System, achieved through a multicomponent, likelihood-based modeling of the data. This supports the hypothesis that R136 is indeed a very powerful cosmic-ray accelerator. Moreover, from the same analysis, we provide an updated measurement of the γ -ray emission from 30 Dor C, the only superbubble detected at TeV energies presently. The γ -ray luminosity above 0.5 TeV of both sources is (2–3) × 10 ^35 erg s ^−1 . This exceeds by more than a factor of 2 the luminosity of HESS J1646−458, which is associated with the most massive young star cluster in the Milky Way, Westerlund 1. Furthermore, the γ -ray emission from each source is extended with a significance of >3 σ and a Gaussian width of about 30 pc. For 30 Dor C, a connection between the γ -ray emission and the nonthermal X-ray emission appears likely. Different interpretations of the γ -ray signal from R136 are discussed.

The dendrochemical approach holds significant promise for determining the geographical origin of wood as a complementary tool to dendroprovenancing based on tree-ring width. Tracing the origin of wood based on its elemental and isotopic composition is in particular interesting for provenance studies at the regional scale, as dendrochemical signatures are indicative of geological and pedological characteristics. Although, absorption of nutrients and trace elements reflects the composition of soil bioavailable pools, it is also modulated by multiple environmental and tree related factors. We assess the dendrochemical approach in oak wood provenance studies regarding the challenges posed by 1) geochemical variation at a local level, and 2) dendrochemical variation related to oak species, age and social status. A combination of 13 elemental concentrations and 2 isotope - Sr and Nd - ratios was analyzed in oak wood from 12 forests situated in the large Seine river catchment in France. The sampling targeted sites with representative types of geological parent material, where adult trees of two common temperate Quercus species (Quercus petraea and Quercus robur) were selected. The impact of tree characteristics was markedly weaker than that of the site factor and the minimal differences in dendrochemical composition between Quercus petraea and Quercus robur were considered without effect on determination of the geographical origin. Linear discriminant analysis based on Ca-normalized elemental concentrations and Sr and Nd isotope ratios correctly classified the origin of 93 % of the sampled trees. Strontium isotope ratio 87 Sr/ 86 Sr was the strongest provenance indicator capable of determining the origin of 55 % of wood samples on its own. Our system based on elemental and strontium and neodymium isotopic compositions provides robust indicators for wood tracing and might be applied to provenance studies in environment, physiology, history and archeology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

After kidney transplantation, conversion to belatacept is a promising alternative in patients with poor graft function or intolerance to calcineurin inhibitors. The risk of acute rejection has not been well described under these conditions. Here we present a retrospective multicenter study investigating the occurrence of acute rejection after conversion in 901 patients (2011-2021). The incidence of cellular and humoral rejection was 5.2% and 0.9%, respectively. T-cell mediated rejection (TCMR) occurred after a median of 2.6 months after conversion. Out of 47 patients with TCMR, death-censored graft survival was 70.1%, 55.1% and 50.8% at 1 year, 3 years and 5 years post-rejection, respectively. Eight patients died after rejection, mainly from infectious diseases. We compared these 47 patients with a cohort of kidney transplant recipients who were converted to belatacept between 2011 and 2017 and did not develop rejection (n = 238). In multivariate analysis, shorter time between KT and conversion, and the absence of anti-thymocyte globulin induction after KT were associated with the occurrence of TCMR after belatacept conversion. The occurrence of rejection after conversion to belatacept appeared to be less frequent than with de novo use. Nevertheless, the risk of graft loss could be significant in patients with already low renal function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bertrand, Chavarot, Olagne, Greze, Gatault, Danthu, Colosio, Jaureguy, Duveau, Bouvier, Le Meur, Golbin, Thervet, Thierry, François, Laurent, Lemoine, Anglicheau and Guerrot.)

Progress towards hepatitis B virus (HBV) global elimination has been slow and most countries are far to reach the elimination targets set up by the World Health Organization (WHO). The burden of chronic hepatitis B is mainly bear by resource-limited countries where only a minority of people living with HBV are diagnosed and treated and international guidelines hardly applicable in real-life. In March 2024, the WHO released its revised guidelines for the prevention and management of chronic hepatitis B. Simplification of care and expansion of treatment criteria represent the core of this revision. Whether and how these updated WHO guidelines will influence the international liver societies (EASL, AASLD and APASL) for their next hepatitis B recommendations remain uncertain. Yet, the European, American and Asian regions encompass multiple low, middle and intermediate-income countries with high HBV endemicity and vulnerable populations that should benefit from simplified clinical algorithms. Here, from an analysis of the WHO guideline development process and its new recommendations, we aimed to identify the anticipated areas of agreements and controversies with the next liver society hepatitis B guidelines which will have to balance clinical risks and benefits for the patients., Competing Interests: Declaration of Competing Interest: Grace Wong has served as an advisory committee member for AstraZeneca, Gilead Sciences, GlaxoSmithKline, Janssen and Virion Biotherapeutics, as a speaker for Abbott, AbbVie, Ascletis, Bristol-Myers Squibb, Echosens, Ferring, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche. She has also received a research grant from Gilead Sciences. Maud Lemoine has served as a consultant for Cepheid, Abbott and Gilead Sciences., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis., Methods: Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011-14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma., Findings: 943 HBsAg-positive people with chronic hepatitis B were recruited to the PROLIFICA study. Of these 943, 58 (6%) fulfilled 2012 EASL treatment eligibility criteria at baseline, 35 (4%) were ineligible for treatment but received antiviral therapy, and 44 (5%) were immediately lost to follow-up. Thus, 806 (85%) participants were analysed for the primary outcome (486 [60%] were male and 320 [40%] were female). After a median follow-up of 6·11 years (IQR 5·34-6·80), 708 (88%) participants were confirmed to be alive at last surveillance, 71 (9%) were lost to follow-up and were censored, and 27 (3%) died, giving an all-cause mortality rate of 582 per 100 000 person-years (95% CI 399-849). Of the 27 people who died, five (19%) had liver-related deaths. Of 708 participants confirmed to be alive, 544 (77%) attended follow-up and were assessed for the secondary outcome. Disease progression occurred in 36 (7%) participants: five (1%) became newly eligible for antiviral therapy per EASL 2017 criteria without liver fibrosis progression; 18 (3%) had liver fibrosis progression alone; 13 (2%) had liver fibrosis progression and newly fulfilled the treatment criteria; and none had hepatic decompensation or developed hepatocellular carcinoma. In multivariable analysis adjusted for sex and age, only a baseline HBV DNA of 20 000 IU/mL or more, compared with the baseline HBV DNA of 2000 IU/mL or lower as the reference, was significantly associated with liver disease progression (odds ratio 5·39, 95% CI 1·37-21·23)., Interpretation: Among people with chronic hepatitis B who were ineligible for antiviral therapy in The Gambia, all-cause mortality and liver disease progression were low. The clinical benefit of expanding antiviral therapy in this subgroup of patients remains uncertain., Funding: European Commission, Medical Research Council UK Research and Innovation, and Gilead Sciences., Competing Interests: Declaration of interests ML, YS, MT, and GN received research funding and consultancy fees from Gilead Sciences and Abbott. ML received consultancy fees from Cepheid and Abbott and is the recipient of the funding. YS received research materials from Fujirebio and Abbott. GC is an employee of Abbott. PI received consultancy fees from Gilead, AbbVie, and ViiV Healthcare. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: DTYL reports support from ICE HBV for travel to present this work at COLDA 2023. AK reports grants from CANSA Cancer Association of South Africa, consulting fees from Roche Diagnostics, and support for attending meetings from Virology Education, University of Witwatersrand, and WHO. MLem reports consulting fees from Abbott and honoraria from Cepheid for lectures and presentations. GM reports grants from ViiV and Jannsen. CSC reports grants from GSK, Gilead Sciences, Janssen, and Roche Pharmaceuticals, and has participated in a data safety monitoring board for GSK. MH reports grants from Gilead Sciences and AbbVie. DAA reports being an inventor on Burnet Institute patents for alanine aminotransferase point of care tests for liver disease (PCT/IB2017/055943) and for dimeric IgA point of care tests for liver cirrhosis (PCT/AU2021/050037), and stock in Nanjing DeShi Diagnostic Technology Co. Ltd, which has licensed the alanine aminotransferase point-of-care test patents from Burnet Institute for manufacture and sale in China. PAR reports grants from NHMRC and a patent pending for CRISPR Cas13b guides targeting HBV (2023901165). CWS reports support by Gilead Sciences to attend AASLD. MLev reports honoraria from AbbVie and Gilead for lectures and presentations and support for attending meetings from AbbVie, Madrigal, and Gilead. ME-S reports support by Gilead Sciences. All other authors declared no competing interests.

Hepatitis B virus (HBV) infection is a major cause of premature death worldwide. In 2016, the World Health Organization (WHO) called for HBV elimination and set up very ambitious elimination targets. The development of effective vaccines, accurate diagnostic tools and safe antiviral drugs make HBV elimination a realistic goal. However, the most constrained-resource regions, which bear the highest burden of HBV, are facing major challenges in implementing strategies to reduce HBV incidence and mortality. Developing simplified approaches adapted to resource-limited settings and scaling up interventions for the prevention and control of HBV globally are urgently needed. Whether HBV elimination will be achieved in an equitable manner and in a reasonable timeframe remains highly uncertain., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare that they have no conflict of interest.

Owing to their rapid cooling rate and hence loss-limited propagation distance, cosmic-ray electrons and positrons (CRe) at very high energies probe local cosmic-ray accelerators and provide constraints on exotic production mechanisms such as annihilation of dark matter particles. We present a high-statistics measurement of the spectrum of CRe candidate events from 0.3 to 40 TeV with the High Energy Stereoscopic System, covering 2 orders of magnitude in energy and reaching a proton rejection power of better than 10^{4}. The measured spectrum is well described by a broken power law, with a break around 1 TeV, where the spectral index increases from Γ_{1}=3.25±0.02(stat)±0.2(sys) to Γ_{2}=4.49±0.04(stat)±0.2(sys). Apart from the break, the spectrum is featureless. The absence of distinct signatures at multi-TeV energies imposes constraints on the presence of nearby CRe accelerators and the local CRe propagation mechanisms.

Background: A novel lattice tip ablation catheter that can toggle between radiofrequency and pulsed-field energy is able to perform not only pulmonary vein isolation, but also linear lesions under general anesthesia (GA)., Objective: We aimed to evaluate the concerns associated with the use of deep sedation and the clinical data related to linear ablation., Methods: Clinical data from two Germany high-volume atrial fibrillation (AF) centers were collected. The objectives of this study are to confirm the feasibility and safety of linear lesion ablation using the lattice tip catheter without GA. Acute procedural and short-term follow-up data were collected., Results: This study included 55 patients who underwent AF ablation (15 with GA vs 40 with deep sedation) including linear lesion ablation for atrial tachyarrhythmia using a lattice tip catheter. Bidirectional block of linear lesions was achieved in 21 of 21 linear lesions in the GA and in 74 of 76 (97%) linear lesions in the deep sedation group (P = 1.000) including roof line in 41 of 41 (100%), posterior wall isolation in 4 of 4 (100%), anterior mitral isthmus (MI) line in 5 of 5 (100%) vs 24 of 25 (96%), posterior MI line in 1 of 1 (100%) vs 4 of 5 (80%), cavotricuspid isthmus line in 15 of 15 (100%), and 1 left atrial appendage isolation. The overall incidence rate of complications was 1.8% (1 cardiac tamponade). There was no other procedural related complication., Conclusion: This preliminary clinical study demonstrates feasibility and safety of bidirectional block of linear lesions using a lattice tip catheter under deep sedation. Need to toggle between energy sources was low., Competing Interests: Disclosures Dr Schmidt is a consultant for—and has received honoraria as well as research funding from—Abbott, Medtronic, Boston Scientific, and Biosense Webster. Dr Bordignon has received honoraria from Medtronic and Biosense Webster. Dr Metzner is a consultant for—and has received honoraria from—Abbott, Medtronic, Boston Scientific, and Biosense Webster. Dr Chun is a consultant for—and has received honoraria as well as research funding from—Abbott, Medtronic, Boston Scientific, and Biosense Webster. The other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The GeneXpert HBV Viral Load test is a simplified tool to scale up screening and HBV monitoring in resource-limited settings, where HBV is endemic and where molecular techniques to quantify HBV DNA are expensive and scarce. However, the accuracy of field diagnostics compared to gold standard assays in HBV-endemic African countries has not been well understood. We aim to validate the diagnostic performance of the GeneXpert HBV Viral Load test in freshly collected and stored plasma and dried blood spot (DBS) samples to assess turn-around-time (TAT) for sample processing and treatment initiation, to map GeneXpert machines and to determine limitations to its use in The Gambia. Freshly collected paired plasma and DBS samples (n = 56) were analyzed by the GeneXpert test. Similarly, stored plasma and DBS samples (n = 306, n = 91) were analyzed using the GeneXpert HBV test, in-house qPCR and COBAS TaqMan Roche. The correlation between freshly collected plasma and DBS is r = 0.88 with a mean bias of -1.4. The GeneXpert HBV test had the highest quantifiable HBV DNA viremia of 81.4% (n = 249/306), and the lowest was detected by in-house qPCR at 37.9% (n = 116/306) for stored plasma samples. Bland-Altman plots show strong correlation between GeneXpert and COBAS TaqMan and between GeneXpert and in-house qPCR with a mean bias of +0.316 and -1.173 log 10 IU/mL, respectively. However, paired stored plasma and DBS samples had a lower mean bias of 1.831 log 10 IU/mL, which is almost significant (95% limits of agreement: 0.66-3.001). Patients (n = 3) were enrolled in the study within a TAT of 6 days. The GeneXpert HBV test displayed excellent diagnostic accuracy by detecting HBV viremia in less than 10 IU/mL.

Background: A novel irrigated radiofrequency balloon (RFB) for pulmonary vein isolation (PVI) integrated into a 3D mapping platform was recently launched., Methods: Patients undergoing a first atrial fibrillation (AF) ablation at two German high-volume EP centers were included into the prospective AURORA registry. All patients underwent clinical follow-up (FU) at 90, 180, and 360 days following ablation including 48-h Holter ECGs., Results: A total of 99 patients were enrolled (43/99 (43.4%) women, median age 67 years (interquartile range [IQR] 59-74), 43/99 (43.4%) persistent AF (Pers-AF), median left ventricular ejection fraction (LVEF) 60% (IQR 62-55)). Eighty-eight patients completed the follow-up. Acute PVI was achieved in 383/383 (100%) PV. Single-shot PVI was achieved in 211/383 (55.1%) PVs. Primary adverse events occurred in 3% of patients (1 postprocedural pharyngeal bleeding, 1 myocardial infarction, 1 non-cardiovascular death); no pericardial effusion, stroke, or phrenic nerve paralysis was observed. Median ablation and procedure times were 23 (IQR 18-32) and 67 (IQR 57-85) min, respectively. Median dose area product was 761 (IQR 509-1534) mGycm 2 . AF-free survival after a median FU of 361 (IQR 261-375) days was 78.4% for paroxysmal AF (PAF) and 75.4% for Pers-AF (p value = 0.828). Early recurrence of atrial tachyarrhythmia at the 90-day visit was the only independent predictor for AF recurrence at 1 year upon multiple regression analysis (hazard ratio [HR] 3.198; 95% confidence interval [95% CI] 1.036-10.32, p value = 0.0433)., Conclusion: RFB-based PVI is acutely successful, appears safe, and has comparable rhythm outcomes to other single-shot AF ablation tools. A recurrence of AF at 90 days predicts later AF recurrence., (© 2024. The Author(s).)

Focal cortical dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-nuclei profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-nuclei dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a distinct neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering directions for targeted therapy development., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Aims: A novel three-dimensional mapping platform combined with a lattice-tip catheter that can toggle between monopolar pulsed field ablation (PFA) and radiofrequency energy delivery was recently launched. So far, the system was predominantly applied in general anaesthesia (GA), not in deep sedation., Methods and Results: Patients with symptomatic paroxysmal or persistent atrial fibrillation (AF) were enrolled, and pulmonary vein isolation (PVI) and ablation of additional linear lesion sets were performed either in GA or in deep sedation. Pulsed field ablation was applied exclusively to perform ipsilateral PVI. A total of 63 patients (35% female, 75% persistent AF, mean age 64 ± 9 years) were included in the analysis with 23 patients treated in GA and 40 patients in deep sedation. Acute efficacy was comparable in both groups with a PVI rate of 100%. Additional 74 lesion sets were performed in the total cohort. Mean procedure and lab occupancy time in the GA and deep sedation group was 96 ± 24 min vs. 100 ± 23 min (P = 0.52) and 165 ± 40 min vs. 131 ± 35 min (P = 0.0008). Mean dose area product was 489 (216;1093) vs. 452 (272;882) cGycm2 in the GA and the deep sedation group (P = 0.82). There was one conversion from deep sedation to GA. There were no map shifts observed in any group. Pericardial tamponade occurred in one patient of the deep sedation group., Conclusion: The use of a novel ablation platform in conjunction with a lattice-tip catheter in deep sedation is feasible, effective, and associated with significantly shorter lab occupancy time when compared with GA., Competing Interests: Conflict of interest: B.S. is a consultant for and has received honoraria as well as research funding from Abbott, Medtronic, Boston Scientific, and Biosense Webster. S.B. has received honoraria from Medtronic and Biosense Webster. K.R.J.C. is a consultant for and has received honoraria as well as research funding from Abbott, Medtronic, Boston Scientific, and Biosense Webster. A.M. is a consultant for and has received honoraria from Abbott, Medtronic, Boston Scientific, and Biosense Webster. A.R. has received travel grants or lecture fees from Medtronic, Ablacon, Abbott, Boston Scientific, Biosense Webster, Pfizer, LifeTech, Bayer, AtriCure, and Novartis. All other authors have nothing to disclose. P.K. was partially supported by European Union MAESTRIA (grant agreement 965286), British Heart Foundation (AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. P.K. received research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last five years. P.K. is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cerebellar atrophy and hypoplasia are usually identified on MRI performed on children presenting signs of cerebellar ataxias, developmental delay, and intellectual disability. These signs can be associated with hypo- or de-myelinating leukodystrophies. A recent study reported two cases: one child diagnosed with leukodystrophy and cerebellar atrophy, harboring a homozygous variant in LSM7, and another who died in utero, presumed to have another homozygous variant in LSM7, based on the parents' genotype. LSM7 encodes a subunit of the LSM complex, involved in pre-RNA maturation and mRNA degradation. Consequently, it has been suggested as a strong candidate disease gene. This hypothesis was supported by functional investigations of the variants. Here, we report a patient with neurodevelopmental defects, leukodystrophy, and cerebellar atrophy, harboring compound heterozygous missense variants in the LSM7 gene. One of these variants is the same as the one carried by the first case reported previously. The other one is at the same position as the variant potentially carried by the second case reported previously. Based on comparable neuroimaging, clinical features, and the involvement of the same amino acids previously demonstrated as key for LSM complex function, we confirm that LSM7 disruption causes a neurodevelopmental disorder characterized by leukodystrophy and cerebellar atrophy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression, trans effects were more tissue-specific than cis effects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cis and trans regulatory evolution., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Glaser-Schmitt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients., Methods: We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival., Results: Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up., Conclusion: PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa., (© 2024. The Author(s).)

Monoclonal antibodies have been administered to kidney transplant recipients (KTRs) with a poor or non-responder status to SARS-CoV-2 vaccination. The cellular response to SARS-CoV-2 has been poorly studied in this context. We assessed the T cell response to SARS-CoV-2 in 97 patients on the day of the injection of tixagevimab/cilgavimab using an IFNγ enzyme-linked immunospot assay (ELISPOT). Among the 97 patients, 34 (35%) developed COVID-19 before the injection. Twenty-nine (85.3%) had an ELISPOT compatible with a SARS-CoV-2 infection. There was no difference between KTRs under belatacept or tacrolimus treatment. Sixty-three patients (64.9%) had no known COVID-19 prior to the ELISPOT, but nine (14.3%) had a positive ELISPOT. In 21 KTRs with a positive ELISPOT who received a booster dose of a bivalent mRNA vaccine, median antibody titers and spike-reactive T cells increased significantly in patients under tacrolimus but not belatacept. Our study emphasizes the potential usefulness of the exploration of immune cellular response to SARS-CoV-2 by ELISPOT. In KTRs with a positive ELISPOT and under CNI therapy, a booster dose of mRNA vaccine seems effective in inducing an immune response to SARS-CoV-2.

Background: Hepatitis B virus (HBV) elimination requires expanding and decentralising HBV care services. However, peripheral health facilities lack access to diagnostic tools to assess eligibility for antiviral therapy. Through the Hepatitis B in Africa Collaborative Network (HEPSANET), we aimed to develop and evaluate a score using tests generally available at lower-level facilities, to simplify the evaluation of antiviral therapy eligibility in people living with HBV., Methods: We surveyed the availability of clinical and laboratory parameters across different health-care levels in sub-Saharan Africa. We used data from the HEPSANET dataset, the largest cross-sectional dataset of treatment-naive people living with HBV in sub-Saharan Africa, to derive and validate the score. Participants from this dataset were included in the analysis if they were aged 18 years or older and had liver fibrosis stages determined by a liver stiffness measurement or liver histopathology. Participants with co-infections or metabolic disorders were excluded. We allocated participants to the derivation and validation sets by geographical site. In the derivation set, we used stepwise logistic regression to identify the best performing parameters for identifying participants that met the 2017 European Association for the Study of the Liver (EASL) criteria. Regression coefficients were converted into integer points to construct simplified algorithms for different health-care levels. In the validation set, we estimated the area under the receiver operating characteristic, sensitivity, and specificity of the simplified algorithm for identifying antiviral therapy eligibility defined by the 2017 EASL criteria., Findings: At 11 sites from eight countries that returned surveys, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were generally available at district hospital levels, and hepatitis B e antigen and point-of-care HBV DNA tests were available only at regional and provincial hospital levels or above. Among 2895 participants included from the HEPSANET database (1740 [60·1%] male, 1155 [39·9%] female), 409 (14·1%) met EASL antiviral therapy eligibility criteria. In the derivation set, the optimal district-level hospital score was: ALT (IU/L), less than 40 (0 points), 40-79 (+1), 80 or greater (+2); AST (IU/L), less than 40 (0), 40-79 (+1), 80 or greater (+2); and platelet counts (10 9 /L), less than 100 (+2), 100-149 (+1), 150 or greater (0). When combined with family history and clinical data for decompensated cirrhosis that do not require any biological tests, a cut-off of 2 points or more had a sensitivity and specificity of 82% (95% CI 76-86) and 95% (93-96) to identify treatment-eligible individuals in the derivation set, and 78% (71-85) and 87% (86-89) in the validation set, respectively., Interpretation: Using a score incorporating platelet counts, AST, and ALT, the majority of people living with HBV requiring antiviral therapy can be identified. Our findings suggest that clinical staging can be decentralised down to district hospital level in sub-Saharan Africa., Funding: European Association for the Study of the Liver Foundation, John C Martin Foundation., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CWS has received speaker bureau honoraria from Gilead Sciences and Abbott, as well as travel support from Gilead Sciences. ES has received a research grant from Gilead Sciences. GW has received a research grant from Roche Diagnostics, Roche Molecular, and Gilead Sciences, and consulting fees from Gilead Sciences, Merck Sharp and Dohme, and ViiV. MA has received research grants from Prenetics, Pfizer, and Johnson & Johnson; consulting fees from Prenetics; honoraria from Pfizer; travel support from WHO; reports planned patents for Ramanomics and LAMP GC/CT/HSV/HBV; and is an unpaid board member of the Charity E3 initiative. MSo has received speaker bureau honoraria from Roche and Gilead Sciences, and travel support from Gilead Sciences. MV has received funding from the US National Institutes of Health (R01AI147727), and travel support from Africa Centres for Disease Control and Prevention. PCM has received funding from the Wellcome Trust (110110) and the Francis Crick Institute, and also reports sponsorship from GSK for a doctoral student, outside the scope of the current work. YS has received a research grant and honoraria for lectures from Gilead Sciences and research materials from Abbott Laboratories and Fujirebio. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Kidney transplant recipients (KTRs) are likely to develop severe COVID-19 and are less well-protected by vaccines than immunocompetent subjects. Thus, the use of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) to confer a passive immunity appears attractive in KTRs. Methods: This retrospective monocentric cohort study was conducted between 1 January 2022 and 30 September 2022. All KTRs with a weak antibody response one month after three doses of mRNA vaccine (anti spike IgG < 264 (BAU/mL)) have received tixagevimab-cilgavimab in pre-exposure (group 1), post-exposure (group 2) or no specific treatment (group 3). We compared COVID-19 symptomatic hospitalizations, including intensive care unit hospitalizations, oxygen therapy, and death, between the three groups. Results: A total of 418 KTRs had SARS-CoV-2 infection in 2022. During the study period, we included 112 KTRs in group 1, 40 KTRs in group 2, and 27 KTRs in group 3. The occurrence of intensive care unit hospitalization, oxygen therapy, and COVID-19 death was significantly increased in group 3 compared to group 1 or 2. In group 3, 5 KTRs (18.5%) were admitted to the intensive care unit, 7 KTRs (25.9%) needed oxygen therapy, and 3 KTRs (11.1%) died. Patients who received tixagevimab-cilgavimab pre- or post-exposure had similar outcomes. Conclusions: This retrospective real-life study supports the relative effectiveness of tixagevimab-cilgavimab on COVID-19 infection caused by Omicron, used as a pre- or post-exposure therapy. The continued evolution of Omicron variants has made tixagevimab-cilgavimab ineffective and reinforces the need for new therapeutic monoclonal antibodies for COVID-19 active on new variants.

Background: Global elimination of hepatitis B virus (HBV) requires expanded uptake of antiviral therapy, potentially by simplifying testing algorithms, especially in resource-limited countries. We evaluated the effectiveness, cost-effectiveness, and budget impact of three strategies that determine eligibility for anti-HBV treatment, as compared with the WHO 2015 treatment eligibility criteria, in The Gambia., Methods: We developed a microsimulation model of natural history using data from the Prevention of Liver Fibrosis and Cancer in Africa programme (known as PROLIFICA) in The Gambia, for an HBV-infected cohort of individuals aged 20 years. The algorithms included in the model were a conventional strategy using the European Association for the Study of the Liver (EASL) 2017 criteria, a simplified algorithm using hepatitis B e antigen and alanine aminotransferase (the Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score), a Treat All approach for all HBV-infected individuals, and the WHO 2015 criteria. Outcomes to measure effectiveness were disability-adjusted life years (DALYs) and years of life saved (YLS), which were used to calculate incremental cost-effectiveness ratios (ICERs) with the WHO 2015 criteria as the base-case scenario. Costs were assessed from a modified social perspective. A budget impact analysis was also done. We tested the robustness of results with a range of sensitiviy analyses including probabilistic sensitivity analysis., Findings: Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted and Treat All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for Treat All (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0·5 times the country's gross domestic product per capita: $352). These patterns did not change when YLS was the outcome. In a modelled cohort of 5000 adults (aged 20 years) with chronic HBV infection from The Gambia, the 5-year budget impact was $1·14 million for Treat All, $0·66 million for TREAT-B, $1·03 million for the WHO criteria, and $1·16 million for the EASL criteria. Probabilistic sensitivity analysis indicated that among the Treat All, EASL, and TREAT-B algorithms, Treat All would become the most preferred strategy only with a willingness-to-pay threshold exceeding approximately $72 000 per DALY averted or $110 000 per YLS., Interpretation: Although the Treat All strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy such as TREAT-B might be a cost-saving alternative., Funding: UK Research and Innovation (Medical Research Council)., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests LBLN has received personal fees from Sanofi and Pfizer for speaker or consultant roles. ML has received research grants from Gilead Sciences and Abbott Laboratories. YS has received consulting fees from WHO, research grants from Gilead Sciences, and research materials from Abbott Laboratories and Fujirebio. SN has received a research grant from Gavi and consulting fees from WHO. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licence. Published by Elsevier Ltd.. All rights reserved.)

We simulate, using a particle-in-cell code, the chain of acceleration processes at work during the Compton-based interaction of a dilute electron-ion plasma with an extreme-intensity, incoherent γ-ray flux with a photon density several orders of magnitude above the particle density. The plasma electrons are initially accelerated in the radiative flux direction through Compton scattering. In turn, the charge-separation field from the induced current drives forward the plasma ions to near-relativistic speed and accelerates backwards the nonscattered electrons to energies easily exceeding those of the driving photons. The dynamics of those energized electrons is determined by the interplay of electrostatic acceleration, bulk plasma motion, inverse Compton scattering and deflections off the mobile magnetic fluctuations generated by a Weibel-type instability. The latter Fermi-like effect notably gives rise to a forward-directed suprathermal electron tail. We provide simple analytical descriptions for most of those phenomena and examine numerically their sensitivity to the parameters of the problem.