Project description:The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.
Project description:Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public-private research collaborations, including public-private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public-private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients.
Project description:Dietary studies can reveal valuable information on how species exploit their habitats and are of particular importance for insular endemics conservation as these species present higher risk of extinction. Reptiles are often neglected in island systems, principally the ones inhabiting remote areas, therefore little is known on their ecological networks. The Selvagens gecko Tarentola (boettgeri) bischoffi, endemic to the remote and integral reserve of Selvagens Archipelago, is classified as Vulnerable by the Portuguese Red Data Book. Little is known about this gecko's ecology and dietary habits, but it is assumed to be exclusively insectivorous. The diet of the continental Tarentola species was already studied using classical methods. Only two studies have used next-generation sequencing (NGS) techniques for this genus thus far, and very few NGS studies have been employed for reptiles in general. Considering the lack of information on its diet and the conservation interest of the Selvagens gecko, we used morphological and DNA metabarcoding approaches to characterize its diet. The traditional method of morphological identification of prey remains in faecal pellets collected over a longer period was compared with metabarcoding of samples collected during rapid surveys. Molecular results revealed that this species is a generalist, feeding on invertebrate, plant and vertebrate items, whereas the morphological approaches were unable to detect the latter two. These results opened up new questions on the ecological role of the Selvagens gecko that deserves to be further explored, such as the possible predation on seabirds, plant services or trophic competition with the sympatric Madeira lizard Teira dugesii. Metabarcoding identified a greater diversity of dietary items at higher taxonomic resolution, but morphological identification enabled calculation of relative abundances and biomasses of ingested arthropods, and detected a dietary shift on invertebrate preys between seasons. Results of this study highlight the global applicability of rapid metabarcoding surveys for understudied taxa on remote islands that are difficult to access. We recommend using the metabarcoding approach, even if 'speedy' sampling only is possible, but we must highlight that disregarding long-term ecological data may lead to 'hasty' conclusion.
Project description:(1) Objectives: to investigate the main lessons learned from the public health (PH) response to COVID-19, using the global perspective endorsed by the WHO pillars, and understand what countries have learned from their practical actions. (2) Methods: we searched for articles in PubMed and CINAHL from 1 January 2020 to 31 January 2022. 455 articles were included. Inclusion criteria were PH themes and lessons learned from the COVID-19 pandemic. One hundred and forty-four articles were finally included in a detailed scoping review. (3) Findings: 78 lessons learned were available, cited 928 times in the 144 articles. Our review highlighted 5 main lessons learned among the WHO regions: need for continuous coordination between PH institutions and organisations (1); importance of assessment and evaluation of risk factors for the diffusion of COVID-19, identifying vulnerable populations (2); establishment of evaluation systems to assess the impact of planned PH measures (3); extensive application of digital technologies, telecommunications and electronic health records (4); need for periodic scientific reviews to provide regular updates on the most effective PH management strategies (5). (4) Conclusion: lessons found in this review could be essential for the future, providing recommendations for an increasingly flexible, fast and efficient PH response to a healthcare emergency such as the COVID-19 pandemic.
Project description:A new strain of coronavirus (COVID-19) emerged in 2020 changing the way the nation looked, worked and lived. In response to this unprecedented COVID-19 pandemic, the Army Nurse Corps (ANC) reexamined our capabies and agility to respond to a new and rapidly evolving environment. Maintaining the pivot to readiness, providing sustainable support and protecting our most valuable asset-our people-were and continues to be in the forefront of leaders' thoughts as we faced this invisible adversary. With every new challenge, lessons learned provide an opportunity to re-examine challenges and successes of the response to COVID-19. Organizational restructuring, balancing risks, expanding capabilities and educational platforms were reassessed and adjusted to fill the needs of the environment as they evolved. The year 2020 will stand throughout history as another example where our readiness, resilience, and flexibility as an Army Nurse Corps was tried and tested. We demonstrated our ability to adapt and overcome-displaying our willingness to stand up as part of the Army Medicine Team and face an unknown adversary to protect the nation we vowed to serve.
Project description:Purpose of this reviewWe discuss the role of observational studies and cardiac registries during the COVID-19 pandemic. We focus on published cardiac registries and highlight contributions to the field that have had clinical implications.Recent findingsWe included observational studies of COVID-19 patients published in peer-reviewed medical journals with defined inclusion and exclusion criteria, defined study design, and primary outcomes. A PubMed and MEDLINE literature review results in 437 articles, of which 52 include patients with COVID-19 with cardiac endpoints. From July 2020 to December 2021, the average time from last data collected to publication was 8.9 ± 4.1 months, with an increasing trend over time (R = 0.9444, p < 0.0001). Of the 52 articles that met our inclusion criteria, we summarize main findings of 4 manuscripts on stroke, 14 on acute coronary syndrome, 4 on cardiac arrest, 7 on heart failure, 7 on venous thromboembolism, 5 on dysrhythmia, and 11 on different populations at risk for cardiovascular. Registries are cost effective, not disruptive to essential health services, and can be rapidly disseminated with short intervals between last data point collected and publication. In less than 2 years, cardiac registries have filled important gaps in knowledge and informed the care of COVID-19 patients with cardiovascular conditions.
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and virulent human-infecting coronavirus that emerged in late December 2019 in Wuhan, China, causing a respiratory disease called coronavirus disease 2019 (COVID-19), which has massively impacted global public health and caused widespread disruption to daily life. The crisis caused by COVID-19 has mobilized scientists and public health authorities across the world to rapidly improve our knowledge about this devastating disease, shedding light on its management and control, and spawned the development of new countermeasures. Here we provide an overview of the state of the art of knowledge gained in the last 2 years about the virus and COVID-19, including its origin and natural reservoir hosts, viral etiology, epidemiology, modes of transmission, clinical manifestations, pathophysiology, diagnosis, treatment, prevention, emerging variants, and vaccines, highlighting important differences from previously known highly pathogenic coronaviruses. We also discuss selected key discoveries from each topic and underline the gaps of knowledge for future investigations.
Project description:The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or human proteins to control viral infection, encompassing hundreds of potential drugs and thousands of patients in clinical trials. So far, a few small-molecule antiviral drugs (nirmatrelvir-ritonavir, remdesivir and molnupiravir) and 11 monoclonal antibodies have been marketed for the treatment of COVID-19, mostly requiring administration within 10 days of symptom onset. In addition, hospitalized patients with severe or critical COVID-19 may benefit from treatment with previously approved immunomodulatory drugs, including glucocorticoids such as dexamethasone, cytokine antagonists such as tocilizumab and Janus kinase inhibitors such as baricitinib. Here, we summarize progress with COVID-19 drug discovery, based on accumulated findings since the pandemic began and a comprehensive list of clinical and preclinical inhibitors with anti-coronavirus activities. We also discuss the lessons learned from COVID-19 and other infectious diseases with regard to drug repurposing strategies, pan-coronavirus drug targets, in vitro assays and animal models, and platform trial design for the development of therapeutics to tackle COVID-19, long COVID and pathogenic coronaviruses in future outbreaks.
Project description:BackgroundCOVID-19 patients requiring mechanical ventilation may develop significant pneumomediastinum and sub-cutaneous emphysema without associated pneumothorax (SWAP). Prophylactic chest tube placement or sub-fascial "blowholes" are usually recommended to prevent tension pneumothorax and clinical decline. Risk of iatrogenic lung injury and release of virus into the environment is high. Incidence and conservative management data of such barotraumatic complications during the COVID-19 pandemic are lacking.MethodsAll patients with mediastinal air and SWAP evaluated by the department of Thoracic Surgery at the Mount Sinai Hospital between March 30 and April 10, 2020 were identified. All patients without pneumothorax were treated conservatively with daily chest x-ray and observation. Three patients had prophylactic chest tube placement prior to the study period without thoracic surgery consultation.ResultsThere were 29 cases of mediastinal air with SWAP out of 171 COVID positive intubated patients (17.0%) who were treated conservatively. Patients were intubated for an average of 2.4 days before SWAP was identified. 12 patients (41%) had improvement or resolution without intervention. Two patients progressed to pneumothorax 3 and 8 days following initial presentation. Both had chest tubes placed without incident before there were any changes in oxygenation, hemodynamics, supportive medications, or ventilator settings. There were 3 patients who had percutaneous tubes placed before the study period all of whom had significant worsening of their sub-cutaneous air and air leak.ConclusionsConservative management of massive sub-cutaneous emphysema without pneumothorax in COVID-19 patients is safe and limits viral exposure to healthcare workers. Placement of chest tubes is discouraged unless a definite sizable pneumothorax develops.