Metatranscriptomics reveals metabolic adaptation and induction of virulence factors by Haemophilus parasuis during lung infection

International audienceAbstractHaemophilus parasuis is a common inhabitant of the upper respiratory tract of pigs, and the causative agent of Glässer’s disease. This disease is characterized by polyserositis and arthritis, produced by the severe inflammation caused by the systemic spread of the bacterium. After an initial colonization of the upper respiratory tract, H. parasuis enters the lung during the early stages of pig infection. In order to study gene expression at this location, we sequenced the ex vivo and in vivo H. parasuis Nagasaki transcriptome in the lung using a metatranscriptomic approach. Comparison of gene expression under these conditions with that found in conventional plate culture showed generally reduced expression of genes associated with anabolic and catabolic pathways, coupled with up-regulation of membrane-related genes involved in carbon acquisition, iron binding and pathogenesis. Some of the up-regulated membrane genes, including ABC transporters, virulence-associated autotransporters (vtaAs) and several hypothetical proteins, were only present in virulent H. parasuis strains, highlighting their significance as markers of disease potential. Finally, the analysis also revealed the presence of numerous antisense transcripts with possible roles in gene regulation. In summary, this data sheds some light on the scarcely studied in vivo transcriptome of H. parasuis, revealing nutritional virulence as an adaptive strategy for host survival, besides induction of classical virulence factors

The conservation status of the world's freshwater molluscs

With the biodiversity crisis continuing unchecked, we need to establish levels and drivers of extinction risk, and reassessments over time, to effectively allocate conservation resources and track progress towards global conservation targets. Given that threat appears particularly high in freshwaters, we assessed the extinction risk of 1428 randomly selected freshwater molluscs using the IUCN Red List Categories and Criteria, as part of the Sampled Red List Index project. We show that close to one-third of species in our sample are estimated to be threatened with extinction, with highest levels of threat in the Nearctic, Palearctic and Australasia and among gastropods. Threat levels were higher in lotic than lentic systems. Pollution (chemical and physical) and the modification of natural systems (e.g. through damming and water abstraction) were the most frequently reported threats to freshwater molluscs, with some regional variation. Given that we found little spatial congruence between species richness patterns of freshwater molluscs and other freshwater taxa, apart from crayfish, new additional conservation priority areas emerged from our study. We discuss the implications of our findings for freshwater mollusc conservation, the adequacy of a sampled approach and important next steps to estimate trends in freshwater mollusc extinction risk over time

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Cerebral lymphoma presenting as a leukoencephalopathy

Cerebral lymphoma is infrequent in immunocompetent patients. This tumour usually appears on CT and MRI as a single lesion or as multiple lesions with mass effect and homogeneous enhancement after contrast administration. A patient is described with a cerebral lymphoma, confirmed by histopathological examination, who presented as a progressive leukoencephalopathy.


The fusion fascia of Fredet: an important embryological landmark for complete mesocolic excision and D3-lymphadenectomy in right colon cancer

Background: The fusion fascia of Toldt is a well-known landmark used by colorectal surgeons. On the contrary, the fusion fascia of Fredet (the plane between the ascending mesocolon and the visceral duodenal-pancreatic peritoneum) still remains a neglected embryological structure. Aim of this study was to provide an anatomic description of this fascia and its application to minimally invasive D3-lymphadenectomy (D3-L) and complete mesocolic excision (CME) for right colon cancer. Methods: First phase: Cadaveric dissection and anatomic description of the fascia of Fredet. Second phase: prospective evaluation of its surgical application in a consecutive series of laparoscopic right hemicolectomies with CME and D3-L at a tertiary hospital. Results: The fascia of Fredet was identified and dissected in one fresh and two formalin-fixed cadavers. The trunk of Henle and the medial border of the superior mesenteric vein defined the medial limit of this embryologic plane. Seventeen patients were operated on. Laparoscopic dissection of the fascia of Fredet was possible in every patient. Median operative time was 210 (120–380) min. There were no major postoperative complications. All cases were adenocarcinomas, except one adenomatous polyp. T stage was Tis in three, T2 in two, T3 in seven, and T4 in five patients. Median number of harvested lymph nodes was 24 (9–39). Lymphatic invasion was found in six patients. All resections were classified as satisfactory mesocolic excision and R0. Median postoperative length of stay was 6 (4–20) days. Median follow-up time was 28 (16–41) months. Local and distal recurrence rate was 0. Conclusion: The fusion fascia of Fredet is useful to achieve CME and D3-L in right colon cancers with reduced risk of intraoperative complications. This structure is particularly suitable for minimally invasive surgery; therefore, we encourage awareness of the fascia of Fredet by colorectal surgeons

Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation : A Retrospective Cohort on Behalf of the Grupo Español de Trasplante Hematopoyetico

Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE ± 4.7%). Multivariate analysis identified active disease status (P <.001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P <.001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P <.05) for OS. The use of myeloablative conditioning (P =.01), active disease (P =.02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P =.009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P =.001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P <.001) and time to second transplantation (P <.001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT did not appear to change outcome, but using an HLA-identical sibling donor for a second transplantation appears to be associated with better survival. Further studies are warranted

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs

Ligand-target prediction by structural network biology using nAnnoLyze

Target identification is essential for drug design, drug-drug interaction prediction, dosage adjustment and side effect anticipation. Specifically, the knowledge of structural details is essential for understanding the mode of action of a compound on a target protein. Here, we present nAnnoLyze, a method for target identification that relies on the hypothesis that structurally similar binding sites bind similar ligands. nAnnoLyze integrates structural information into a bipartite network of interactions and similarities to predict structurally detailed compound-protein interactions at proteome scale. The method was benchmarked on a dataset of 6,282 pairs of known interacting ligand-target pairs reaching a 0.96 of area under the Receiver Operating Characteristic curve (AUC) when using the drug names as an input feature for the classifier, and a 0.70 of AUC for "anonymous" compounds or compounds not present in the training set. nAnnoLyze resulted in higher accuracies than its predecessor, AnnoLyze. We applied the method to predict interactions for all the compounds in the DrugBank database with each human protein structure and provide examples of target identification for known drugs against human diseases. The accuracy and applicability of our method to any compound indicate that a comparative docking approach such as nAnnoLyze enables large-scale annotation and analysis of compound-protein interactions and thus may benefit drug development