51 research outputs found
William Lenthall, 1591-1640: the apprenticeship of a Stuart speaker.
No full textThe thesis examines the first fifty years of the life of William Lenthall (1591-1662), Speaker of the House of Commons during the Long Parliament. In attempting to provide the necessary background for consideration of Lenthall's Speakership, the study traces the development of a career which has received little attention, but which was an essential preparation for Lenthall's entrance into public life. -- Lenthall is shown to have served two apprenticeships for his later role. The first was in his chosen profession of the law; the second, which was shared by many other Englishmen of his class and time, was his increasing participation in local and county government. Each of these apprenticeships reinforced the other and, with brief but active committee work in two parliaments before November, 1640, made Lenthall a more suitable choice as Speaker than later writers have suggested. -- Parallel and crucial to the chronological discussion of Lenthall's career is an examination of his personal contacts during the period. Local and professional associates are traced, as well as family connections, and the resulting case study of gentry relationships demonstrates the extent to which such relationships were themselves an important qualification for public office. It is further suggested that the continual interplay of these connections affords a significant clue to the cohesiveness before 1640 of the Stuart gentry and the strength of this class as an effective parliamentary force. -- The thesis, which ends as Lenthall's public career begins, does not propose to solve the many questions of interpretation raised by Lenthall's Speakership. It is intended, instead, to provide a context in which these questions may at last be considered.Bibliography : leaves 230-245
An investigation into violence against nurses in the southern region of Malawi Chimwemwe Chikoko.
No full textIncludes bibliographical references.Incidences of violence in nursing have been reported in local media in Malawi. Although violence in the health sector is not a new concept, it has become a global concern in the 21st century (Needham, Kingma, O'Brien-Pallas, McKenna, Tucker & Oud, 2008:6). The aim of the study was to investigate and describe the nature and extent of violence against nurses and the perceived effects thereof on nurses in selected health facilities in the southern region of Malawi
Global impact of the COVID-19 pandemic on subarachnoid haemorrhage hospitalisations, aneurysm treatment and in-hospital mortality: 1-year follow-up
No full textAvailable to read at the publisher's website here: https://doi.org/10.1136/jnnp-2022-329200.Background Prior studies indicated a decrease in the incidences of aneurysmal subarachnoid haemorrhage (aSAH) during the early stages of the COVID-19 pandemic. We evaluated differences in the incidence, severity of aSAH presentation, and ruptured aneurysm treatment modality during the first year of the COVID-19 pandemic compared with the preceding year. Methods We conducted a cross-sectional study including 49 countries and 187 centres. We recorded volumes for COVID-19 hospitalisations, aSAH hospitalisations, Hunt-Hess grade, coiling, clipping and aSAH in-hospital mortality. Diagnoses were identified by International Classification of Diseases, 10th Revision, codes or stroke databases from January 2019 to May 2021. Results Over the study period, there were 16 247 aSAH admissions, 344 491 COVID-19 admissions, 8300 ruptured aneurysm coiling and 4240 ruptured aneurysm clipping procedures. Declines were observed in aSAH admissions (-6.4% (95% CI-7.0% to-5.8%), p=0.0001) during the first year of the pandemic compared with the prior year, most pronounced in high-volume SAH and high-volume COVID-19 hospitals. There was a trend towards a decline in mild and moderate presentations of subarachnoid haemorrhage (SAH) (mild:-5% (95% CI-5.9% to-4.3%), p=0.06; moderate:-8.3% (95% CI-10.2% to-6.7%), p=0.06) but no difference in higher SAH severity. The ruptured aneurysm clipping rate remained unchanged (30.7% vs 31.2%, p=0.58), whereas ruptured aneurysm coiling increased (53.97% vs 56.5%, p=0.009). There was no difference in aSAH in-hospital mortality rate (19.1% vs 20.1%, p=0.12). Conclusion During the first year of the pandemic, there was a decrease in aSAH admissions volume, driven by a decrease in mild to moderate presentation of aSAH. There was an increase in the ruptured aneurysm coiling rate but neither change in the ruptured aneurysm clipping rate nor change in aSAH in-hospital mortality. Trial registration number NCT04934020.Copyright © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.https://doi.org/10.1136/jnnp-2022-32920
Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production
No full textAntibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.sponsorship: This work was supported by National Health and Medical Research Council (NHMRC) program grants (1016953 and 1113904 to S.G. Tangye, R. Brink, and C.C. Goodnow), NHMRC project grants (1088215 to E.K. Deenick; 1127157 to S.G. Tangye and E.K. Deenick), NHMRC Principal Research Fellowships (1042925 to S.G. Tangye; 1105877 to R. Brink), a Fulbright Senior Scholarship (to S.G. Tangye), the Office of Health and Medical Research of the New South Wales Government, the Jeffrey Modell Foundation, the John Brown Cook Foundation, the Ross Trust, and a Bench-to-Bedside grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. G. Uzel and L.D. Notarangelo are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. (National Health and Medical Research Council (NHMRC)|1016953, National Health and Medical Research Council (NHMRC)|1113904, NHMRC|1088215, NHMRC|1127157, NHMRC|1042925, NHMRC|1105877, Fulbright Senior Scholarship, Office of Health and Medical Research of the New South Wales Government, Jeffrey Modell Foundation, John Brown Cook Foundation, Ross Trust, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases|ZIAAI001222, National Health and Medical Research Council of Australia|1088215, National Health and Medical Research Council of Australia|1127157, National Health and Medical Research Council of Australia|1105877)status: Publishe
B cell-intrinsic requirement for STK4 in humoral immunity in mice and human subjects
No full text[Abstract Not Availabe]National Health and Medical Research Council (NHMRC) [1139865]; Office of Health and Medical Research of the NSW State Government; John Cook Brown Foundation; Jeffrey Modell Foundation; National Health and Medical Research Council of Australia [1139865] Funding Source: NHMRCSupported by National Health and Medical Research Council (NHMRC) grant ID1139865, the Office of Health and Medical Research of the NSW State Government, the John Cook Brown Foundation, and the Jeffrey Modell Foundation. The contents of this article are solely the responsibility of the authors and do not reflect the views of the NHMRC
Association between anesthesia modality and clinical outcomes following endovascular stroke treatment in the extended time window
No full textBACKGROUND: There is a paucity of data on anesthesia-related outcomes for endovascular treatment (EVT) in the extended window (>6 hours from ischemic stroke onset). We compared functional and safety outcomes between local anesthesia (LA) without sedation, conscious sedation (CS) and general anesthesia (GA). METHODS: Patients who underwent EVT in the early ( Copyright © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.https://doi.org/10.1136/neurintsurg-2022-01884
Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies
No full textThe emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer. Increasing antibody affinity into the low picomolar range endowed potent neutralization of VOCs and protection of hACE2 mice from viral challenge. Cryoelectron microscopy and crystal structures of two affinity-matured antibodies (4C12-B12 and 4G1-C2) in complex with RBD highlighted binding modes and epitopes distal from mutational hotspots commonly overserved in VOCs, providing direct structural insights into the observed mutational resistance. Moreover, we further demonstrate that antibodies targeting the class 6 epitope, rather than being an artifact of in vitro selection, are common in the IgG1+ memory B cell repertoire of convalescent patients and can be induced in human antibody V-gene transgenic mice through immunization. Our results highlight the importance of very high (picomolar) affinity in the development of neutralizing antibodies and vaccines and suggest an affinity threshold in the provision of broad and long-lasting immunity against SARS-CoV-2
Endovascular thrombectomy beyond 24 hours from ischemic stroke onset: a propensity score matched cohort study
No full textBACKGROUND: The safety and functional outcome of endovascular thrombectomy (EVT) in the very late (VL; >24 hours) time window from ischemic stroke onset remains undetermined. METHODS: Using data from a national stroke registry, we used propensity score matched (PSM) individual level data of patients who underwent EVT, selected with CT perfusion or non-contrast CT/CT angiography, between October 2015 and March 2020. Functional and safety outcomes were assessed in both late (6-24 hours) and VL time windows. Subgroup analysis was performed of imaging selection modality in the VL time window. RESULTS: We included 1150 patients (late window: 1046 (208 after PSM); VL window: 104 (104 after PSM)). Compared with EVT treatment initiation between 6 and 24 hours, patients treated in the VL window had similar modified Rankin Scale (mRS) scores at discharge (ordinal shift; common OR=1.08, 95% CI 0.69 to 1.47, p=0.70). No significant differences in achieving good functional outcome (mRS Copyright © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.https://doi.org/10.1136/neurintsurg-2021-01859
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