Optical interactions are governed by both spin and angular momentum conservation laws, which serve as a tool for controlling light-matter interactions or elucidating electron dynamics and structure ...of complex systems. Here, we uncover a form of simultaneous spin and orbital angular momentum conservation and show, theoretically and experimentally, that this phenomenon allows for unprecedented control over the divergence and polarization of extreme-ultraviolet vortex beams. High harmonics with spin and orbital angular momenta are produced, opening a novel regime of angular momentum conservation that allows for manipulation of the polarization of attosecond pulses-from linear to circular-and for the generation of circularly polarized vortices with tailored orbital angular momentum, including harmonic vortices with the same topological charge as the driving laser beam. Our work paves the way to ultrafast studies of chiral systems using high-harmonic beams with designer spin and orbital angular momentum.
The aims of this study were to evaluate health outcomes and the economic burden of hospitalized COVID-19 patients in the United States.
Hospitalized patients with a primary or secondary discharge ...diagnosis code for COVID-19 (ICD-10 code U07.1) from 1 April to 31 October 2020 were identified in the Premier Healthcare COVID-19 Database. Patient demographics, hospitalization characteristics, and concomitant medical conditions were assessed. Hospital length of stay (LOS), in-hospital mortality, hospital charges, and hospital costs were evaluated overall and stratified by age groups, insurance types, and 4 COVID-19 disease progression states based on intensive care unit (ICU) and invasive mechanical ventilation (IMV) usage.
Of the 173,942 hospitalized COVID-19 patients, the median age was 63 years, 51.0% were male, and 48.5% were covered by Medicare. The most prevalent concomitant medical conditions were cardiovascular disease (73.5%), hypertension (64.8%), diabetes (40.7%), obesity (27.0%), and chronic kidney disease (24.2%). Approximately one-fifth (21.9%) of the hospitalized COVID-19 patients were admitted to the ICU and 16.9% received IMV; most patients (73.6%) did not require ICU admission or IMV, and 12.4% required both. The median hospital LOS was 5 days, in-hospital mortality was 13.6%, median hospital charges were $43,986, and median hospital costs were $12,046. Hospital LOS and in-hospital mortality increased with ICU and/or IMV usage and age; hospital charges and costs increased with ICU and/or IMV usage. Patients with both ICU and IMV usage had the longest median hospital LOS (15 days), highest in-hospital mortality (53.8%), and highest hospital charges ($198,394) and hospital costs ($54,402).
This retrospective administrative database analysis relied on coding accuracy and a subset of admissions with validated/reconciled hospital costs.
This study summarizes the severe health outcomes and substantial hospital costs of hospitalized COVID-19 patients in the US. The findings support the urgent need for rapid implementation of effective interventions, including safe and efficacious vaccines.
The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially impacted healthcare utilization worldwide. The objective of this ...retrospective analysis of a large hospital discharge database was to compare all-cause and cause-specific hospitalizations during the first six months of the pandemic in the United States with the same months in the previous four years.
Data were collected from all hospitals in the Premier Healthcare Database (PHD) and PHD Special Release reporting hospitalizations from January through July for each year from 2016 through 2020. Hospitalization trends were analyzed stratified by age group, major diagnostic categories (MDCs), and geographic region.
The analysis included 286 hospitals from all 9 US Census divisions. The number of all-cause hospitalizations per month was relatively stable from 2016 through 2019 and then fell by 21% (57,281 fewer hospitalizations) between March and April 2020, particularly in hospitalizations for non-respiratory illnesses. From April onward there was a rise in the number of monthly hospitalizations per month. Hospitalizations per month, nationally and in each Census division, decreased for 20 of 25 MDCs between March and April 2020. There was also a decrease in hospitalizations per month for all age groups between March and April 2020 with the greatest decreases in hospitalizations observed for patients 50-64 and ≥65 years of age.
Rates of hospitalization declined substantially during the first months of the COVID-19 pandemic, suggesting delayed routine, elective, and emergency care in the United States. These lapses in care for illnesses not related to COVID-19 may lead to increases in morbidity and mortality for other conditions. Thus, in the current stage of the pandemic, clinicians and public-health officials should work, not only to prevent SARS-CoV-2 transmission, but also to ensure that care for non-COVID-19 conditions is not delayed.
Inflammatory bowel diseases (IBDs) exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. We ...aimed to determine the past current, and future prevalences of IBD in Canada.
We performed a retrospective cohort study using population-based health administrative data from Alberta (2002–2015), British Columbia (1997–2014), Manitoba (1990–2013), Nova Scotia (1996–2009), Ontario (1999–2014), Quebec (2001–2008), and Saskatchewan (1998–2016). Autoregressive integrated moving average regression was applied, and prevalence, with 95% prediction intervals (PIs), was forecasted to 2030. Average annual percentage change, with 95% confidence intervals, was assessed with log binomial regression.
In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716–735) and annual average percent change was estimated at 2.86% (95% confidence interval 2.80%–2.92%). The prevalence in 2030 was forecasted to be 981 per 100,000 (95% PI 963–999): 159 per 100,000 (95% PI 133–185) in children, 1118 per 100,000 (95% PI 1069–1168) in adults, and 1370 per 100,000 (95% PI 1312–1429) in the elderly. In 2018, 267,983 Canadians (95% PI 264,579–271,387) were estimated to be living with IBD, which was forecasted to increase to 402,853 (95% PI 395,466–410,240) by 2030.
Forecasting prevalence will allow health policy makers to develop policy that is necessary to address the challenges faced by health systems in providing high-quality and cost-effective care.
Determining whether SARS-CoV-2 exhibits seasonality like other respiratory viruses is critical for public health planning. We evaluated whether COVID-19 rates follow a seasonal pattern using time ...series models. We used time series decomposition to extract the annual seasonal component of COVID-19 case, hospitalization, and mortality rates from March 2020 through December 2022 for the United States and Europe. Models were adjusted for a country-specific stringency index to account for confounding by various interventions. Despite year-round disease activity, we identified seasonal spikes in COVID-19 from approximately November through April for all outcomes and in all countries. Our results support employing annual preventative measures against SARS-CoV-2, such as administering seasonal booster vaccines in a similar timeframe as those in place for influenza. Whether certain high-risk individuals may need more than one COVID-19 vaccine booster dose each year will depend on factors like vaccine durability against severe illness and levels of year-round disease activity.
Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability ...of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA.
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•CD8 T cells with an enhanced affinity TCR readily infiltrate and accumulate in PDA•Mesothelin-targeted T cells induce tumor cell lysis and stromal involution•T cell therapy increases survival in KPC mice without chemotherapy or radiation•Analogously engineered T cells with mesothelin-specific TCR lyse human PDA cells
Stromnes et al. show in preclinical models that T cells engineered to express affinity-enhanced T cell receptors against mesothelin overcome physical and immunologic barriers to treat pancreatic ductal adenocarcinoma. Serial adoptive transfers of these cells are safe and significantly increase overall survival.
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19
relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant ...tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to ...joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with ...several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 μM range in vitro. Furthermore, Exebryl-1, a ß-amyloid anti-aggregation molecule for Alzheimer's therapy, was shown to have antiviral activity between 10 to 66 μM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.
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