Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The alteplase dose assessment for Pleural infection Therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22–58] to 16% [8–31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247–2,984] over 72 h of therapy; P <  0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pl

COVID-19: looking beyond the peak. Challenges and tips for radiologists in follow-up of a novel patient cohort

As the coronavirus pandemic evolves, the focus of radiology departments has begun to change. The acute phase of imaging a new disease entity whilst rationalising radiology services in the face of lockdown has passed. Radiologists are now becoming familiar with the complications of COVID-19, particularly the lung parenchymal and pulmonary vascular sequelae and are considering the impact follow-up imaging may have on departments already struggling with a backlog of suspended imaging in the face of reduced capacity. This review from the British Society of Thoracic Imaging explores both the thoracic and extra-thoracic complications of COVID-19, recognising the importance of a holistic approach to patient follow-up. The British Thoracic Society guidelines for respiratory follow-up of COVID-19 will be discussed, together with newly developed reporting templates, which aim to provide consistency for clinicians as well as an opportunity for longer-term data collection

Deletion of Complement Factor H–Related Genes CFHR1 and CFHR3 Is Associated with Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H–related 1 (CFHR1) and complement factor H–related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of ∼84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes

Corporate governance and financial constraints on strategic turnarounds

The paper extends the Robbins and Pearce (1992) two-stage turnaround response model to include governance factors. In addition to the retrenchment and recovery, the paper proposes the addition of a realignment stage, referring specifically to the re-alignment of expectations of principal and agent groups. The realignment stage imposes a threshold that must be crossed before the retrenchment and hence recovery stage can be entered. Crossing this threshold is problematic to the extent that the interests of governance-stakeholder groups diverge in a crisis situation. The severity of the crisis impacts on the bases of strategy contingent asset valuation leading to the fragmentation of stakeholder interests. In some cases the consequence may be that management are prevented from carrying out turnarounds by governance constraints. The paper uses a case study to illustrate these dynamics, and like the Robbins and Pearce study, it focuses on the textile industry. A longitudinal approach is used to show the impact of the removal of governance constraints. The empirical evidence suggests that such financial constraints become less serious to the extent that there is a functioning market for corporate control. Building on governance research and turnaround literature, the paper also outlines the general case necessary and sufficient conditions for successful turnarounds