The S.h.i.v.e.r.i.n.g. Trials: A Novel Vaccine Strategy And Analysis Of Serologic Durability In Patients With Plasma Cell Dyscrasias

ABSTRACT Background: Patients with plasma cell dyscrasias are at an increased risk for infections due to their dysfunctional immune system. Each year these vulnerable patients are advised to receive the flu shot, but this vaccine has been shown to induce a serologic response that is not sufficiently protective in these patients. More effective methods for vaccinating patients with plasma cell dyscrasias are necessary. Methods: The Study of High-Dose Influenza Vaccine Efficacy by Repeated dosing IN Gammopathy patients (SHIVERING 1) Pilot Trial was implemented at the Yale Cancer Center during the 2014-2015 flu season. Patients with plasma cell dyscrasias (n=51) received the high-dose inactivated trivalent influenza vaccine followed by a booster dose of that same vaccine 30 days later. The SHIVERING 2 randomized, double-blind, placebo-controlled, interventional trial was implemented at the Yale Cancer Center during the 2015-2016 flu season. The experimental arm (n=81) received the two dose regimen and the control arm (n=41) received the standard of care. In both trials, patients were followed throughout the flu season for evidence of flu infections, and sera was collected for hemagglutinin titer analysis and correlation with clinical characteristics and patient demographics. Results: SHIVERING 1 demonstrated that the double high-dose regimen was safe and resulted in significantly higher rates of seroprotection than have been previously reported. There were no grade 2 adverse events. The seroprotection rate increased from 4% at baseline, to 47% after the first vaccine, and to 65% after the second vaccine. SHIVERING 2 demonstrated significantly higher rates of seroprotection at day 60 and a lower rate of laboratory confirmed flu infections in the experimental arm versus the control arm. Analysis of the durability of serologic protection demonstrated a significant difference in HAI titer growth and direction between the two arms, with the standard of care arm experiencing a decline in HAI titer levels during the day 30 to day 60 interval following vaccine administration. Additionally, patients with early disease in the experimental arm were significantly more likely to remain seroprotected at study end than patients with advanced disease in the control arm. Finally, patients that are female and those that had undergone an autotransplant in the past were significantly more likely to remain seroprotected at study end. Conclusion: These trials suggest that a boosted high-dose influenza vaccine regimen is safe and results in lower rates of infection and higher rates of seroprotection in patients with plasma cell disorders. Patients with early stage disease are able to mount a more durable serologic response than patients with advanced disease. Larger studies will be needed to confirm these preliminary findings

Infectious Fear: The Rhetoric of Pestilence in Middle English Didactic Texts on Death

This article examines literary references to bubonic plague in a sample of late fourteenth- and fifteenth-century English texts that are didactic in tone and address the theme of death, including Geoffrey Chaucer’s “The Pardoner’s Tale”, John Lydgate’s “Danse Macabre” and the anonymous The Castle of Perseverance and “A Disputation between the Body and Worms”. Although there have been broad surveys of bubonic plague in Middle English literature, as well as studies of isolated texts, this article is the first to examine the role of pestilence in a group of texts linked by theme and authorial intention. It contributes to current understanding of the disease in late medieval literature and culture, showing how authors utilised the idea of pestilence as a frightening cause of sudden death and as a form of rhetoric serving to encourage readers to reflect on mortality, the spiritual health of the soul and the prospect of salvation. Whereas previous research has shown that doctors, priests and writers interpreted the pestilence as a divine punishment for sin, this study demonstrates how that belief could be exploited for rhetorical purposes. The rhetoric of pestilence emerges as a powerful contemplative tool urging readers to practise self-examination, penitence and a more active, strategic approach to death

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of Mycobacterium tuberculosis isolates from KwaZulu-Natal.

CAPRISA, 2015.Abstract available in pdf

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Joseph Berington and the English Catholic Cisalpine Movement, 1772-1803.

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Searching HathiTrust: Old Concepts in a New Context

This paper examines the use of the HathiTrust Digital Library as a resource for locating primary sources in the course of historical research. It focuses on the incorporation of library metadata into HathiTrust database records and the benefits this has on search strategies. The author outlines a method for locating primary sources that reduces information overload and allows researchers to target specific types of documents commonly used by historians. Historians report turning more and more frequently to open book repositories to find relevant material for their research, but also that searching full text databases often leads to information overload. The case study presented demonstrates that HathiTrust provides not only a rich collection of primary sources, but also that its inclusion of Library of Congress Subject Headings creates a uniquely effective means of searching them with higher recall and precision. Despite their usefulness, the author identifies some limitations to searching LCSH in HathiTrust and makes recommendations for overcoming them. Librarians in academic environments should promote the informed use of HathiTrust among their faculty as a way of providing superior research support and improving collaboration between researchers and librarians