Safety, tolerability, and activity of the active C1s antibody riliprubart in cold agglutinin disease: a phase 1b study.

ABSTRACT: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by complement pathway-mediated hemolysis. Riliprubart (SAR445088, BIVV020), a second-generation classical complement inhibitor, is a humanized monoclonal antibody that selectively inhibits only the activated form of C1s. This Phase 1b study evaluated the safety, tolerability, and effect on hemolysis of riliprubart in adult patients with cold agglutinin disease. On day 1, 12 patients received a single IV dose of either 30 mg/kg (n = 6) or 15 mg/kg (n = 6) of riliprubart and were subsequently followed for 15 weeks. Riliprubart was generally well tolerated; there were no treatment-emergent serious adverse events, or treatment-emergent adverse events leading to death or permanent study discontinuation. There were no reports of serious infections, encapsulated bacterial infections including meningococcal infections, hypersensitivity, or thromboembolic events. Rapid improvements in hemoglobin (day 5) and bilirubin (day 1) were observed in both treatment cohorts. Mean hemoglobin levels were maintained at >11.0 g/dL from day 29 and mean levels of bilirubin were normalized by day 29; both responses were maintained throughout the study. Improvements in clinical markers closely correlated with a sustained reduction in the 50% hemolytic complement (CH50) throughout the study. Mean C4 levels, an in vivo marker of treatment activity, increased 1 week after treatment with either dose of riliprubart and were sustained throughout the study. In conclusion, a single IV dose of riliprubart was well tolerated, and led to rapid classical complement inhibition, control of hemolysis, and improvement in anemia, all of which were sustained over 15 weeks. This trial was registered at www.ClinicalTrials.gov as #NCT04269551.

Building a Covid-19 secure intensive care unit: A human-centred design approach.

Background: The Covid-19 pandemic has highlighted weaknesses in the National Health Service critical care provision including both capacity and infrastructure. Traditionally, healthcare workspaces have failed to fully incorporate Human-Centred Design principles resulting in environments that negatively affect the efficacy of task completion, patient safety and staff wellbeing. In the summer of 2020, we received funds for the urgent construction of a Covid-19 secure critical care facility. The aim of this project was to design a pandemic resilient facility centred around both staff and patient requirements and safety, within the available footprint. Methods: We developed a simulation exercise, underpinned by Human-Centred Design principles, to evaluate intensive care designs through Build Mapping, Tasks Analysis and Qualitative data. Build Mapping involved taping out sections of the design and mocking up with equipment. Task Analysis and qualitative data were collected following task completion. Results: 56 participants completed the build simulation exercise generating 141 design suggestions (69 task related, 56 patient and relative related, 16 staff related). Suggestions translated to 18 multilevel design improvements; five significant structural changes (Macro level) including wall moves and lift size change. Minor improvements were made at a Meso and Micro design level. Critical care design drivers identified included functional drivers (visibility, Covid-19 secure environment, workflow, and task efficiency) and behavioural drivers (learning and development, light, humanising intensive care and design consistency). Conclusion: Success of clinical tasks, infection control, patient safety and staff/patient wellbeing are highly dependent on clinical environments. Primarily, we have improved clinical design by focusing on user requirements. Secondly, we developed a replicable approach to exploring healthcare build plans revealing significant design changes, that may have only been identified once built.

Using real-time location devices (RTLD) to quantify off-unit adult intensive care registrar workload: a 1-year tertiary NHS hospital prospective observational study.

UK national guidelines state deteriorating or at risk hospital ward patients should receive care from trained critical care outreach personnel. In most tertiary hospitals this involves a team led by an Intensive Care Unit (ICU) registrar. The ICU registrar must also review patients referred for possible ICU admission. These two responsibilities require work away from the ICU. To our knowledge the burden of this work has not been described, despite its importance in ICU workforce management and patient safety. A 12-month, prospective, observational study was carried out. The primary outcome measure was ICU registrar time spent on and off-unit. The study participants were senior and junior registrars on the rota of the 16 bed, Adult Intensive Care Unit at the John Radcliffe Hospital in Oxford. To measure their work patterns, this study used AeroScout 'T2' Real Time Location Device (RTLD) tags (Stanley Healthcare, Swindon). In our hospital, senior and junior ICU registrars spend roughly one-fifth of their time off-unit, half of which is spent in ED. This workload combines to leave the unit unattended at night up to 10% of the time. RTLDs provide a reliable, automated method for quantifying ICU registrar off-unit work patterns. This method may be adopted for quantifying other clinical staff work patterns in suitably equipped hospital environments.

Thoracic ultrasound competence for ultrasound-guided pleural procedures.

Focused thoracic ultrasound has become essential in the guidance and direction of pleural interventions to reduce unwanted complications and as a result now forms a crucial component of physician training. Current training standards along with assessment methods vary widely, and are often not robust enough to ensure adequate competence.This review assesses the current state of training and assessment of thoracic ultrasound competence in various settings, allowing comparison with alternative competency based programmes. Future directions for training and assessment of thoracic ultrasound competence are discussed.

Clostridium perfringens sepsis complicated by right ventricular cardiogenic shock.

Clostridium perfringens sepsis has been ascribed a dismal prognosis when associated with massive intravascular haemolysis. We present a 71-year-old woman's fatal case which was compounded by isolated right ventricular cardiogenic shock. In this context, combined use of transthoracic echocardiography and pulmonary artery catheter monitoring is able to yield an individualized hemodynamic resuscitation. We discuss key aspects related to right and left heart mechanical efficiency, hypothesize as to the pulmonary hypertension mechanism of our case and set to emphasize a physiologically based framework for right ventricular failure hemodynamic management.

Point-of-care ultrasound: its growing application in hospital medicine.

Point-of-care ultrasound is emerging as an important adjunct to the clinical examination. Ultrasonography has long been seen as a modality for experts but this is changing and it is hoped that, with appropriate training, point-of-care ultrasound will become a modern-day diagnostic necessity.

Hepatic capsular rupture in pregnancy.

The syndrome of haemolysis, elevated liver enzymes and low platelets is a rare condition specific to pregnancy, affecting approximately 5-20% of all pre-eclamptic pregnancies. Described here is a woman in her first pregnancy, who experienced an intrauterine death following a significant hepatic haematoma and capsular rupture, in the absence of classical clinical features suggestive of pre-eclampsia. The events that followed suggested haemolysis, elevated liver enzymes and low platelets syndrome as the likely diagnosis. The patient's clinical course highlights the difficulties that may be encountered when making decisions about pregnant women with complicated medical and obstetric issues.

Reexpansion pulmonary edema following local anesthetic thoracoscopy: correlation and evolution of radiographic and ultrasonographic findings.

Local anesthetic (medical) thoracoscopy is used with increasing frequency by pulmonologists worldwide for both diagnostic and therapeutic purposes, notably in comorbid patients who may not be physiologically robust enough for general anesthesia. Understanding the complications that can arise and how to manage them is crucial for any physician performing this procedure. Reexpansion pulmonary edema is a rare but recognized complication of draining pleural effusions and pneumothoraces that has not been described previously in association with physician-led thoracoscopy. This case provides an opportunity for an overview of what is known about this unusual but potentially fatal condition. Data correlating ultrasonographic, radiographic, and clinical progression are also presented to highlight the potential usefulness of ultrasonography in identifying lung parenchymal abnormalities such as extravascular lung water.

Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US.

BACKGROUND: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. OBJECTIVE: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. METHODS: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. RESULTS: THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (∼5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (∼5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. CONCLUSION: Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold.

A primary cardiac sarcoma presenting with superior vena cava obstruction.

Superior vena cava (SVC) obstruction leads to a constellation of symptoms and signs that encompass the SVC syndrome. Today, malignancy accounts for 65% of all cases. The most common neoplastic causes are non­small cell lung cancer (50%), small cell lung cancer (25%), lymphoma, and metastasis. Primary cardiac tumors are an extremely rare cause of SVC obstruction. We describe the case of a 48-year-old man who presented with dyspnea, confusion, and facial swelling with cyanosis. The patient developed life-threatening airway obstruction after administration of anxiolytic. The diagnosis of SVC obstruction secondary to a primary cardiac sarcoma was established based on clinical, radiologic, and post-mortem findings. This is one of very few reported cases of a primary cardiac sarcoma causing SVC obstruction.