The arithmetic topology of genetic alignments.

We propose a novel mathematical paradigm for the study of genetic variation in sequence alignments. This framework originates from extending the notion of pairwise relations, upon which current analysis is based on, to k-ary dissimilarity. This dissimilarity naturally leads to a generalization of simplicial complexes by endowing simplices with weights, compatible with the boundary operator. We introduce the notion of k-stances and dissimilarity complex, the former encapsulating arithmetic as well as topological structure expressing these k-ary relations. We study basic mathematical properties of dissimilarity complexes and show how this approach captures watershed moments of viral dynamics in the context of SARS-CoV-2 and H1N1 flu genomic data.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Data-driven scalable pipeline using national agent-based models for real-time pandemic response and decision support

This paper describes an integrated, data-driven operational pipeline based on national agent-based models to support federal and state-level pandemic planning and response. The pipeline consists of (i) an automatic semantic-aware scheduling method that coordinates jobs across two separate high performance computing systems;(ii) a data pipeline to collect, integrate and organize national and county-level disaggregated data for initialization and post-simulation analysis;(iii) a digital twin of national social contact networks made up of 288 Million individuals and 12.6 Billion time-varying interactions covering the US states and DC;(iv) an extension of a parallel agent-based simulation model to study epidemic dynamics and associated interventions. This pipeline can run 400 replicates of national runs in less than 33 h, and reduces the need for human intervention, resulting in faster turnaround times and higher reliability and accuracy of the results. Scientifically, the work has led to significant advances in real-time epidemic sciences.

In Situ Pulmonary Thrombolysis and Perfusion Lung Angiography in Severe COVID-19 Respiratory Failure.

A proof-of-concept study using thrombolysis with catheter-directed tissue plasminogen activator (tPA) and pulmonary angiography imaging was performed to visualize perfusion deficits and reperfusion/therapeutic effects of tPA. DESIGN: A prospective, open-label, compassionate study. Descriptive statistics were presented for categorical variables and as means with sds for continuous variables. The Wilcoxon test was used to determine the differences between the two-related samples and a t test for continuous variables. Statistical significance was set at p value of less than 0.05. Agreement between observations was evaluated using the Kappa Cohen index and overall agreement using the Fleiss Kappa coefficient. SETTING: A single COVID-19 ICU of Mexico´s General Hospital Dr Eduardo Liceaga. SUBJECTS: Fifteen patients with severe Delta variant severe acute respiratory syndrome coronavirus 2 infection, 18-75 years old, requiring mechanical ventilation with a persistent Fio2 requirement of 70% or higher and Pao2/Fio2 ratio (or imputed ratio) less than 150 for more than 4 hours. The coagulation inclusion criteria were International Society on Thrombosis and Haemostasis score greater than 5, and presence of a d-dimer greater than 1,200, with viscoelastic testing using rotational thromboelastometry (Instrumentation Laboratories, Mexico City, Mexico) showing both hypercoagulability (EXTEM amplitude at 5 min > 65 FIBTEM > 30) and hypofibrinolysis (EXTEM maximum lysis < 8%). INTERVENTIONS: Catheter-directed tPA angiography and iFlow system analysis to assess pre-tPA baseline pulmonary perfusion and changes in response to thrombolysis. RESULTS: Nine patients had microvascular filling defects demonstrated by angiography, and good agreement was found with iFlow analysis (ƙ = 0.714). Statistically significant differences were identified in the area under the curve (AUC) region of interest/AUC reference tissue with and without filling defects in phase 2 DM -0.09206 (sd ± 0.16684) (p = 0.003). The Pao2/Fio2 values measured immediately and 48 hours after the procedure were significantly higher (p = 0.001 and p = 0.005, respectively). Statistically significant differences were found in d-dimer values (p = 0.007), Fio2 (p = 0.002), and oxygen saturation in arterial blood/Fio2 (p = 0.045), as well as in the number of patients who required prone positioning before, immediately after the procedure, and at 48 hours after the procedure (p = 0.002). CONCLUSIONS: Thrombolysis with catheter-directed tPA resulted in imaging evidence via pulmonary angiography and iFlow technology of improved lung perfusion in COVID-19 patients with severe respiratory failure.

Therapists in the Uniformed Services: Improving Care in Emergency Response Medical Missions.

People diagnosed with COVID-19 who require hospitalization are primarily admitted secondary to shortness of breath because of hypoxia but also display difficulties with overall muscle weakness, which could impair gait, activities of daily living, speech, cognitive-linguistics, or swallowing. This article provides a clinical perspective of how a physical therapist, occupational therapist, and speech language pathologist in the US Public Health Service Commissioned Corps were deployed with an augmentation team and how they improved care at a hospital that was overwhelmed with patients diagnosed with COVID-19. The rehabilitation team completed 246 evaluation and treatment encounters in a 12-day period and began seeing patients within 24 hours on-site. After the rehabilitation team arrived, patients were noted to be more mobile, independent in activities of daily living, and able to tolerate the least restrictive diets without signs and symptoms of aspiration. As a result of rehabilitation services, safe discharges were expedited, length of stay was reduced, and the hospitals' inpatient admission capacity was maximized. The augmentation team learned the importance of including rehabilitation specialties for treating patients with COVID-19. Mobilizing rehabilitation specialties along with medical and nursing staff helps maximize the overall recovery, health, and outcomes for patients. Leadership that is responsible for the development and deployment of future medical teams in military, emergency response, and public health efforts should consider all therapy disciplines as an essential component for each team.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.

Journal submissions, review and editorial decision patterns during initial COVID-19 restrictions.

We use the full administrative records from four leading agricultural economics journals to study the impacts of the COVID-19 pandemic on manuscript submission, editorial desk rejection and reviewer acceptance rates, and time to editorial decision. We also test for gender differences in these impacts. Manuscript submissions increased sharply and equi-proportionately by gender. Desk rejection rates remained stable, leading to increased demand for reviews. Female reviewers became eight percentage points more likely to decline a review invitation during the early stage of the pandemic. First editorial decisions for papers sent out for peer review occurred significantly faster after pandemic lockdowns began. Overall, the initial effects of the pandemic on journal editorial tasks and review patterns appear relatively modest, despite the increased number of submissions handled by editors and reviewers. We find no evidence in agricultural economics of a generalized disruption to near-term, peer-reviewed publication.

Neurosurgery in octogenarians during the COVID-19 pandemic: Results from a tertiary care trauma centre.

BACKGROUND: In 2020, 6% of Scotland's adult population was ≥80 years. Advancements in care mean improved chances of survival at 6-months for older adults following injury to the brain or spine. The Covid-19 pandemic also resulted in local and national policies aimed at protecting the elderly. We sought to evaluate referral patterns and outcomes for patients ≥80 years referred to our institution during this period. OBJECTIVE: To evaluate referral patterns and outcomes for patients ≥80 years referred to our institution both before and during the coronavirus pandemic. DESIGN: Retrospective observational cohort study. SETTING: Tertiary care in a developing major trauma centre (Queen Elizabeth University Hospital, Glasgow). PARTICIPANTS: All patients ≥80 years referred to the on-call neurosurgical service over two four-month periods before (2016-17; n = 1573) and after the onset of Covid-19 (2020; n = 2014). METHODS: Data on demographics, ASA, diagnosis and referral decision were collected. 30-day and 6-month mortality and functional independence were assessed. RESULTS: 246 (before) and 335 (during Covid-19) referred patients were ≥80 years. No gender bias. A significant increase (17%) in acute trauma was seen during the pandemic months. Fewer older adults were transferred (6% to 2% Covid-19) for specialist care, most commonly for chronic subdural haematoma. Most were alive, home and independent at 6 months (47% pre and 63% during Covid-19). CONCLUSIONS: Octogenarians feature disproportionately in acute adult neurosurgical referrals. In our department, local and national responses to the Covid-19 pandemic did not appear to influence this. Robust evidence of neurosurgical outcomes in the older adult is required to fairly distribute resources for our ageing population, but decisions must not be based on age alone.

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series.

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.

Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non-COVID-19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow-up trial using the widely available tissue-type plasminogen activator (t-PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population. Objective: To describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS. Patients/Methods: A rapidly adaptive, pragmatic, open-label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO2 ratio <150 mm Hg for > 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. Results: The primary outcome is improvement in PaO2/FiO2 at 48 hours after randomization. Other outcomes include ventilator- and intensive care unit-free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with 4 looks at the data. Conclusion: Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).

Multiscale Feedback Loops in SARS-CoV-2 Viral Evolution.

COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral genome is considered to be relatively stable and the mutations that have been observed and reported thus far are mainly focused on the coding region. This article provides evidence that macrolevel pandemic dynamics, such as social distancing, modulate the genomic evolution of SARS-CoV-2. This view complements the prevalent paradigm that microlevel observables control macrolevel parameters such as death rates and infection patterns. First, we observe differences in mutational signals for geospatially separated populations such as the prevalence of A23404G in CA versus NY and WA. We show that the feedback between macrolevel dynamics and the viral population can be captured employing a transfer entropy framework. Second, we observe complex interactions within mutational clades. Namely, when C14408T first appeared in the viral population, the frequency of A23404G spiked in the subsequent week. Third, we identify a noncoding mutation, G29540A, within the segment between the coding gene of the N protein and the ORF10 gene, which is largely confined to NY (>95%). These observations indicate that macrolevel sociobehavioral measures have an impact on the viral genomics and may be useful for the dashboard-like tracking of its evolution. Finally, despite the fact that SARS-CoV-2 is a genetically robust organism, our findings suggest that we are dealing with a high degree of adaptability. Owing to its ample spread, mutations of unusual form are observed and a high complexity of mutational interaction is exhibited.

COVID-19: All the wrong moves in all the wrong places.

In this Editorial, Barrett and Yaffe highlight shortcomings in our collective response to the COVID-19 pandemic and underscore the need for more basic research into this new disease.

Fibrinolytic therapy for refractory COVID-19 acute respiratory distress syndrome: Scientific rationale and review.

The coronavirus disease 2019 (COVID-19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID-19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure. Numerous studies are ongoing focusing on anticytokine therapies, antibiotics, and antiviral agents, but none to date have focused on treating the underlying thrombotic coagulopathy in an effort to improve respiratory failure in COVID-19. There are animal data and a previous human trial demonstrating a survival advantage with fibrinolytic therapy to treat acute respiratory distress syndrome. Here, we review the extant and emerging literature on the relationship between thrombotic coagulopathy and pulmonary failure in the context of COVID-19 and present the scientific rationale for consideration of targeting the coagulation and fibrinolytic systems to improve pulmonary function in these patients.

Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis.

BACKGROUND: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO2/FiO2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. METHODS: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO2/FiO2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. RESULTS: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios. CONCLUSIONS: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.

Rescue Therapy for Severe COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS) with Tissue Plasminogen Activator (tPA): A Case Series

The COVID-19 pandemic has led to unprecedented stresses on modern medical systems, overwhelming the resource infrastructure in numerous countries while presenting a unique series of pathophysiologic clinical findings. Thrombotic coagulopathy is common in critically ill patients suffering from COVID-19, with associated high rates of respiratory failure requiring prolonged periods of mechanical ventilation. Here we report a case series of five patients suffering from profound, medically refractory COVID-19 associated respiratory failure who were treated with fibrinolytic therapy using tissue plasminogen activator (tPA, Alteplase). All five patients appeared to have an improved respiratory status following tPA administration: one patient had an initial marked improvement that partially regressed after several hours, one patient had transient improvements that were not sustained, and three patients had sustained clinical improvements following tPA administration.