On December 2, 2015, a terror attack in the city of San Bernardino, California killed 14 Americans and injured 22 in the deadliest attack on U.S. soil since September 11, 2001. Although emergency ...personnel and law enforcement officials frequently deal with multi-casualty incidents (MCIs), what occurred that day required an unprecedented response. Most of the severely injured victims were transported to either Loma Linda University Medical Center (LLUMC) or Arrowhead Regional Medical Center (ARMC). These two hospitals operate two designated trauma centers in the region and played crucial roles during the massive response that followed this attack. In an effort to shed a light on our response to others, we provide an account of how these two teaching hospitals prepared for and coordinated the medical care of these victims. In general, both centers were able to quickly mobilize large number of staff and resources. Prior disaster drills proved to be invaluable. Both centers witnessed excellent teamwork and coordination involving first responders, law enforcement, administration, and medical personnel from multiple specialty services. Those of us working that day felt safe and protected. Although we did identify areas we could have improved upon, including patchy communication and crowd-control, they were minor in nature and did not affect patient care. MCIs pose major challenges to emergency departments and trauma centers across the country. Responding to such incidents requires an ever-evolving approach as no two incidents will present exactly alike. It is our hope that this article will foster discussion and lead to improvements in management of future MCIs.
Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, ...waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them.
The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney ...xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti‐pig antibodies significantly improved survival in a pig‐to–rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan–T cell depletion and an anti‐CD154–based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long‐term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti‐pig antibody and CD4 depletion resulted in consistent, long‐term xenograft survival.
CD4 T cell depletion is critical to long‐term (beyond 1 year) survival of pig‐to‐nonhuman primate kidney xenografts.
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal ...microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α
β
integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.
The COVID-19 pandemic poses unique challenges within the austere clinical setting, and the time between patient presentation and deterioration is a critical opportunity for intervention. In some ...cases, this may be a life-saving transfer to a higher level of care. US Central Command (CENTCOM) has provided valuable guidance for COVID-19 management in the operational environment,1 and has proposed the National Early Warning System 2 (NEWS2) scoring tool as a useful adjunct to gauging illness severity. NEWS2, however, does not consider co-morbidities, such as diabetes or chronic cardiac disease, which could worsen the clinical course of SARS-CoV-2 patients. Thus, NEWS2 fails to address such factors during the risk stratification of patients to a higher level of care. To address this concern, June 2020, 3rd Medical Brigade, Operation Spartan Shield (OSS) developed the COVID-19 Army Rapid Assessment Tool (CARAT) with inputs from clinicians and researchers (The Team). The CARAT is a clinical scoring system, modified from the NEWS2, which combines the effects of co-morbid disease with the current physiological condition of a COVID-19 patient. The Team obtained clinical data for 105 patients from the CENTCOM area of responsibility (AOR), who presented to a military treatment facility (MTF) symptomatic for, and testing positive for SARS-CoV-2, during the time period of June to mid-August 2020. Each patient was retrospectively assigned a CARAT score based on his or her initial presentation. Preliminary review of data suggested a CARAT value of 4 or greater was an indicator for risk of further deterioration. Patients were then grouped into two categories: patients who received transfer to a higher level of care, versus "stay-in-place" supportive care. Results showed that 100% of patients with a score ≥4 had been transferred to a higher echelon of care, compared to 2% of patients with scores less than 4. A Fisher's exact test demonstrated a statistically significant difference between these two groups (p is less than 0.001). Interestingly, when compared with the NEWS2 score, the CARAT identified 9 individuals for transfer to a higher level of care, of whom only one patient was identified by the NEWS2, clearly underscoring the significance of CARAT despite small sample size. We therefore recommend that CARAT be further validated in predicting disease severity and need for emergent evacuation in larger patient settings.
The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004-2007.
Routinely collected population-based ...data were obtained on all adults (15-99 years) diagnosed with lung cancer in 2004-2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis.
Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer.
There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.
Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial ...responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.
Mountain lakes are often situated in protected natural areas, a feature that leads to their role as sentinels of global environmental change. Despite variations in latitude, mountain lakes share many ...features, including their location in catchments with steep topographic gradients, cold temperatures, high incident solar and ultraviolet radiation (UVR), and prolonged ice and snow cover. These characteristics, in turn, affect mountain lake ecosystem structure, diversity, and productivity. The lakes themselves are mostly small, and up until recently, have been characterized as oligotrophic. This paper provides a review and update of the growing body of research that shows that sediments in remote mountain lakes archive regional and global environmental changes, including those linked to climate change, altered biogeochemical cycles, and changes in dust composition and deposition, atmospheric fertilization, and biological manipulations. These archives provide an important record of global environmental change that pre-dates typical monitoring windows. Paleolimnological research at strategically selected lakes has increased our knowledge of interactions among multiple stressors and their synergistic effects on lake systems. Lakes from transects across steep climate (i.e., temperature and effective moisture) gradients in mountain regions show how environmental change alters lakes in close proximity, but at differing climate starting points. Such research in particular highlights the impacts of melting glaciers on mountain lakes. The addition of new proxies, including DNA-based techniques and advanced stable isotopic analyses, provides a gateway to addressing novel research questions about global environmental change. Recent advances in remote sensing and continuous, high-frequency, limnological measurements will improve spatial and temporal resolution and help to add records to spatial gaps including tropical and southern latitudes. Mountain lake records provide a unique opportunity for global scale assessments that provide knowledge necessary to protect the Earth system.
•Mountain lakes are sensitive recorders of global environmental change.•Paleolimnology has benefited from technological advances, with many applications to alpine environments.•Gaps in spatial coverage are evident in the tropics and Southern Hemisphere, where water resource issues are a concern.•Paleolimnology can be used to identify threats to the quantity and quality of mountain reservoirs.•We highlight the complexities of ecosystem responses to the many, interconnected stressors of global environmental change.
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