Effectiveness of emergency surgery for five common acute conditions: an instrumental variable analysis of a national routine database.

The effectiveness of emergency surgery vs. non-emergency surgery strategies for emergency admissions with acute appendicitis, gallstone disease, diverticular disease, abdominal wall hernia or intestinal obstruction is unknown. Data on emergency admissions for adult patients from 2010 to 2019 at 175 acute National Health Service hospitals in England were extracted from the Hospital Episode Statistics database. Cohort sizes were: 268,144 (appendicitis); 240,977 (gallstone disease); 138,869 (diverticular disease); 106,432 (hernia); and 133,073 (intestinal obstruction). The primary outcome was number of days alive and out of hospital at 90 days. The effectiveness of emergency surgery vs. non-emergency surgery strategies was estimated using an instrumental variable design and is reported for the cohort and pre-specified sub-groups (age, sex, number of comorbidities and frailty level). Average days alive and out of hospital at 90 days for all five cohorts were similar, with the following mean differences (95%CI) for emergency surgery minus non-emergency surgery after adjusting for confounding: -0.73 days (-2.10-0.64) for appendicitis; 0.60 (-0.10-1.30) for gallstone disease; -2.66 (-15.7-10.4) for diverticular disease; -0.07 (-2.40-2.25) for hernia; and 3.32 (-3.13-9.76) for intestinal obstruction. For patients with 'severe frailty', mean differences (95%CI) in days alive and out of hospital for emergency surgery were lower than for non-emergency surgery strategies: -21.0 (-27.4 to -14.6) for appendicitis; -5.72 (-11.3 to -0.2) for gallstone disease, -38.9 (-63.3 to -14.6) for diverticular disease; -19.5 (-26.6 to -12.3) for hernia; and - 34.5 (-46.7 to -22.4) for intestinal obstruction. For patients without frailty, the mean differences (95%CI) in days alive and out of hospital were: -0.18 (-1.56-1.20) for appendicitis; 0.93 (0.48-1.39) for gallstone disease; 5.35 (-2.56-13.28) for diverticular disease; 2.26 (0.37-4.15) for hernia; and 18.2 (14.8-22.47) for intestinal obstruction. Emergency surgery and non-emergency surgery strategies led to similar average days alive and out of hospital at 90 days for five acute conditions. The comparative effectiveness of emergency surgery and non-emergency surgery strategies for these conditions may be modified by patient factors

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis

The human CD14+ monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16+ monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by theCD16+CD163+MerTK+pSTAT3+ phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16+CD163+MerTK+pSTAT3+ cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16+CD163+MerTK+pSTAT3+ monocyte-to-macrophage differentiation program and its potential as a target for TB therapy,and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoringof treatment efficacy.Fil: Lastrucci, Claire. Centre National de la Recherche Scientifique; FranciaFil: Bénard, Alan. Centre National de la Recherche Scientifique; FranciaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pingris, Karine. Centre National de la Recherche Scientifique; FranciaFil: Souriant, Shanti. Centre National de la Recherche Scientifique; FranciaFil: Poincloux, Renaud. Centre National de la Recherche Scientifique; FranciaFil: Al Saati, Talal. Inserm; FranciaFil: Rasolofo, Voahangy. Pasteur Institute in Antananarivo; MadagascarFil: González Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Inwentarz, Sandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Kondova, Ivanela. Biomedical Primate Research Centre; Países BajosFil: Verreck, Franck A. W.. Biomedical Primate Research Centre; Países BajosFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Maridonneau Parini, Isabel. Centre National de la Recherche Scientifique; FranciaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Celine. Centre National de la Recherche Scientifique; Franci

Circulating CD14brightCD16+ 'intermediate' monocytes exhibit enhanced parasite pattern recognition in human helminth infection.

Circulating monocyte sub-sets have recently emerged as mediators of divergent immune functions during infectious disease but their role in helminth infection has not been investigated. In this study we evaluated whether 'classical' (CD14brightCD16-), 'intermediate' (CD14brightCD16+), and 'non-classical' (CD14dimCD16+) monocyte sub-sets from peripheral blood mononuclear cells varied in both abundance and ability to bind antigenic material amongst individuals living in a region of Northern Senegal which is co-endemic for Schistosoma mansoni and S. haematobium. Monocyte recognition of excretory/secretory (E/S) products released by skin-invasive cercariae, or eggs, of S. mansoni was assessed by flow cytometry and compared between S. mansoni mono-infected, S. mansoni and S. haematobium co-infected, and uninfected participants. Each of the three monocyte sub-sets in the different infection groups bound schistosome E/S material. However, 'intermediate' CD14brightCD16+ monocytes had a significantly enhanced ability to bind cercarial and egg E/S. Moreover, this elevation of ligand binding was particularly evident in co-infected participants. This is the first demonstration of modulated parasite pattern recognition in CD14brightCD16+ intermediate monocytes during helminth infection, which may have functional consequences for the ability of infected individuals to respond immunologically to infection

A super-Earth and a sub-Neptune orbiting the bright, quiet M3 dwarf TOI-1266

We report the discovery and characterisation of a super-Earth and a sub-Neptune transiting the bright ($K=8.8$), quiet, and nearby (37 pc) M3V dwarf TOI-1266. We validate the planetary nature of TOI-1266 b and c using four sectors of TESS photometry and data from the newly-commissioned 1-m SAINT-EX telescope located in San Pedro M\'artir (Mexico). We also include additional ground-based follow-up photometry as well as high-resolution spectroscopy and high-angular imaging observations. The inner, larger planet has a radius of $R=2.37_{-0.12}^{+0.16}$ R$_{\oplus}$ and an orbital period of 10.9 days. The outer, smaller planet has a radius of $R=1.56_{-0.13}^{+0.15}$ R$_{\oplus}$ on an 18.8-day orbit. The data are found to be consistent with circular, co-planar and stable orbits that are weakly influenced by the 2:1 mean motion resonance. Our TTV analysis of the combined dataset enables model-independent constraints on the masses and eccentricities of the planets. We find planetary masses of $M_\mathrm{p}$ = $13.5_{-9.0}^{+11.0}$ $\mathrm{M_{\oplus}}$ ($<36.8$ $\mathrm{M_{\oplus}}$ at 2-$\sigma$) for TOI-1266 b and $2.2_{-1.5}^{+2.0}$ $\mathrm{M_{\oplus}}$ ($<5.7$ $\mathrm{M_{\oplus}}$ at 2-$\sigma$) for TOI-1266 c. We find small but non-zero orbital eccentricities of $0.09_{-0.05}^{+0.06}$ ($<0.21$ at 2-$\sigma$) for TOI-1266 b and $0.04\pm0.03$ ($<0.10$ at 2-$\sigma$) for TOI-1266 c. The equilibrium temperatures of both planets are of $413\pm20$ K and $344\pm16$ K, respectively, assuming a null Bond albedo and uniform heat redistribution from the day-side to the night-side hemisphere. The host brightness and negligible activity combined with the planetary system architecture and favourable planet-to-star radii ratios makes TOI-1266 an exquisite system for a detailed characterisation

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents.

Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR-ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC(50) on day 5 of 4.6 microg ml(-1) and 3.4 microg ml(-1) for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 microg ml(-1): 55.5+/-8.7 vs 96.4+/-3.7%). STI571 also appeared to specifically target bcr-abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34(+) chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+/-11.3 vs 44.5+/-8.7 and 17.8+/-7.0% in cultures with STI571 and etoposide alone respectively; P<0.001). This study confirms the central oncogenic role of BCR-ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis