Mental Stress Provokes Ischemia in Coronary Artery Disease Subjects Without Exercise- or Adenosine-Induced Ischemia

ObjectivesThe purpose of this study was to investigate the possibility that some patients with coronary artery disease (CAD) but negative exercise or chemical stress test results might have mental stress-induced ischemia. The study population consisted solely of those with negative test results.BackgroundMental stress-induced ischemia has been reported in 20% to 70% of CAD subjects with exercise-induced ischemia. Because mechanisms of exercise and mental stress-induced ischemia may differ, we studied whether mental stress would produce ischemia in a proportion of subjects with CAD who have no inducible ischemia with exercise or pharmacologic tests.MethodsTwenty-one subjects (14 men, 7 women) with a mean age of 67 years and with a documented history of CAD were studied. All subjects had a recent negative nuclear stress test result (exercise or chemical). Subjects completed a speaking task involving role playing a difficult interpersonal situation. A total of 30 mCi 99mTc-sestamibi was injected at one minute into the speech, and imaging was started 40 min later. A resting image obtained within one week was compared with the stress image. Images were analyzed for number and severity of perfusion defects. The summed difference score based on the difference between summed stress and rest scores was calculated. Severity was assessed using a semiquantitative scoring method from zero to four.ResultsSix of 21 (29%) subjects demonstrated reversible ischemia (summed difference score ≥3) with mental stress. No subject had chest pain or electrocardiographic changes during the stressor. Mean systolic and diastolic blood pressure and heart rate all increased between resting and times of peak stress.ConclusionsMental stress may produce ischemia in some subjects with CAD and negative exercise or chemical nuclear stress test results

Defining the next generation of severe malaria treatment: a target product profile.

BACKGROUND: Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa. Hence, new treatments for severe malaria are needed, and it is prudent to define their characteristics now. This manuscript focuses on the target product profile (TPP) for new treatments for severe malaria. It also highlights preparedness when considering ways of protecting the utility of artemisinin-based therapies. TARGET PRODUCT PROFILE: Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings. CONCLUSION: Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease

Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Seismic Analysis of Buried Continuous Pipelines Crossing Fault Stepovers

The response of ductile single degree of freedom (SDOF) structures subjected to spontaneous rupture propagation in two faults with a stepover (both compressional and extensional) is studied. A dynamic rupture simulation is carried by defining the initial stresses on the fault and considering slip-weakening friction laws. Differences in peak ground parameters plots in three orthogonal directions are highlighted. Using the synthetic seismograms that are based on the numerical solution to wave propagation partial differential equation coupled with contact-friction laws, a comparison is made between the right step and left step faulting conditions for variations in contours of elastic (µ=1) and multiple ductility response spectra (µ = 2,4,6,8). Also, an attempt is made to understand the difference in responses of elastic-perfectly-plastic structures by placing stations radially at 5 km (approx.) from the point of origin that lies between the two faults and at different azimuths and performing the time-history analysis. Structures buried inside the ground such as pipelines, tunnels while crossing a fault plane develops both axial and bending strains because of the fault movement. Complex fault geometry like fault stepping at a site can either aggravate or alleviate the response of such structures. In this study, we addressed the influence fault stepping on the behaviour of oil and gas pipeline. Since the existing literature developed pipelines models crossing single fault, considering the fault stepping system as a whole is essential to predict the behaviour of pipeline failures accurately. The seismic analysis was carried out using an analytical approach proposed by Uckan et al. [2015]. Results from the analytical approach clearly show a significant variation in both axial and bending strains along the pipeline axis between the two type of fault stepping – Extensional (also called dilational) and Compressional. It was observed that pipeline develops about 35% and 60% lower bending and axial strains when it crosses a compressional step. Also in the direction parallel to the fault plane, the compressional stepping reduced the pipeline strains. A parametric study of the pipe diameter to thickness ratio (D/t) for critical strains also suggested that pipeline is more likely to buckle within 10 km on either side of the main fault for an extensional case. However, the critical zone length was limited to only 5 km in the case of the compressional stepping, making it a more reliable path of the two alternatives for pipeline design

Improving Death Certificate Completion a Trial of Two Training Interventions

The death certificate is an important medical document that impacts mortality statistics and health care policy. Resident physician accuracy in completing death certificates is poor. We assessed the impact of two educational interventions on the quality of death certificate completion by resident physicians. Two-hundred and nineteen internal medicine residents were asked to complete a cause of death statement using a sample case of in-hospital death. Participants were randomized into one of two educational interventions: either an interactive workshop (group I) or provided with printed instruction material (group II). A total of 200 residents completed the study, with 100 in each group. At baseline, competency in death certificate completion was poor. Only 19% of residents achieved an optimal test score. Sixty percent erroneously identified a cardiac cause of death. The death certificate score improved significantly in both group I (14±6 vs 24±5, pp

Improving Death Certificate Completion a Trial of Two Training Interventions

The death certificate is an important medical document that impacts mortality statistics and health care policy. Resident physician accuracy in completing death certificates is poor. We assessed the impact of two educational interventions on the quality of death certificate completion by resident physicians. Two-hundred and nineteen internal medicine residents were asked to complete a cause of death statement using a sample case of in-hospital death. Participants were randomized into one of two educational interventions: either an interactive workshop (group I) or provided with printed instruction material (group II). A total of 200 residents completed the study, with 100 in each group. At baseline, competency in death certificate completion was poor. Only 19% of residents achieved an optimal test score. Sixty percent erroneously identified a cardiac cause of death. The death certificate score improved significantly in both group I (14±6 vs 24±5, pp