Understanding risk factors for hospitalization in vaccinated persons and the association of COVID-19 vaccines with hospitalization rates is critical for public health efforts to control COVID-19.
To ...determine characteristics of COVID-19-associated hospitalizations among vaccinated persons and comparative hospitalization rates in unvaccinated and vaccinated persons.
From January 1, 2021, to April 30, 2022, patients 18 years or older with laboratory-confirmed SARS-CoV-2 infection were identified from more than 250 hospitals in the population-based COVID-19-Associated Hospitalization Surveillance Network. State immunization information system data were linked to cases, and the vaccination coverage data of the defined catchment population were used to compare hospitalization rates in unvaccinated and vaccinated individuals. Vaccinated and unvaccinated patient characteristics were compared in a representative sample with detailed medical record review; unweighted case counts and weighted percentages were calculated.
Laboratory-confirmed COVID-19-associated hospitalization, defined as a positive SARS-CoV-2 test result within 14 days before or during hospitalization.
COVID-19-associated hospitalization rates among vaccinated vs unvaccinated persons and factors associated with COVID-19-associated hospitalization in vaccinated persons were assessed.
Using representative data from 192 509 hospitalizations (see Table 1 for demographic information), monthly COVID-19-associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. From January to April 2022, when the Omicron variant was predominant, hospitalization rates were 10.5 times higher in unvaccinated persons and 2.5 times higher in vaccinated persons with no booster dose, respectively, compared with those who had received a booster dose. Among sampled cases, vaccinated hospitalized patients with COVID-19 were older than those who were unvaccinated (median IQR age, 70 58-80 years vs 58 46-70 years, respectively; P < .001) and more likely to have 3 or more underlying medical conditions (1926 77.8% vs 4124 51.6%, respectively; P < .001).
In this cross-sectional study of US adults hospitalized with COVID-19, unvaccinated adults were more likely to be hospitalized compared with vaccinated adults; hospitalization rates were lowest in those who had received a booster dose. Hospitalized vaccinated persons were older and more likely to have 3 or more underlying medical conditions and be long-term care facility residents compared with hospitalized unvaccinated persons. The study results suggest that clinicians and public health practitioners should continue to promote vaccination with all recommended doses for eligible persons.
The COVID-19 pandemic has caused substantial morbidity and mortality.
To describe monthly clinical trends among adults hospitalized with COVID-19.
Pooled cross-sectional study.
99 counties in 14 ...states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET).
U.S. adults (aged ≥18 years) hospitalized with laboratory-confirmed COVID-19 during 1 March to 31 December 2020.
Monthly hospitalizations, intensive care unit (ICU) admissions, and in-hospital death rates per 100 000 persons in the population; monthly trends in weighted percentages of interventions, including ICU admission, mechanical ventilation, and vasopressor use, among an age- and site-stratified random sample of hospitalized case patients.
Among 116 743 hospitalized adults with COVID-19, the median age was 62 years, 50.7% were male, and 40.8% were non-Hispanic White. Monthly rates of hospitalization (105.3 per 100 000 persons), ICU admission (20.2 per 100 000 persons), and death (11.7 per 100 000 persons) peaked during December 2020. Rates of all 3 outcomes were highest among adults aged 65 years or older, males, and Hispanic or non-Hispanic Black persons. Among 18 508 sampled hospitalized adults, use of remdesivir and systemic corticosteroids increased from 1.7% and 18.9%, respectively, in March to 53.8% and 74.2%, respectively, in December. Frequency of ICU admission, mechanical ventilation, and vasopressor use decreased from March (37.8%, 27.8%, and 22.7%, respectively) to December (20.5%, 12.3%, and 12.8%, respectively); use of noninvasive respiratory support increased from March to December.
COVID-NET covers approximately 10% of the U.S. population; findings may not be generalizable to the entire country.
Rates of COVID-19-associated hospitalization, ICU admission, and death were highest in December 2020, corresponding with the third peak of the U.S. pandemic. The frequency of intensive interventions for management of hospitalized patients decreased over time. These data provide a longitudinal assessment of clinical trends among adults hospitalized with COVID-19 before widespread implementation of COVID-19 vaccines.
Centers for Disease Control and Prevention.
What is already known about this topic? Immunocompromise is associated with increased risk for intensive care unit (ICU) admission and in-hospital death after SARS-CoV-2 infection. Population-based ...descriptions of immunocompromised hospitalized patients and their outcomes are limited. What is added by this report? Immunocompromised patients accounted for 12.2% of all adult COVID-19 hospitalizations among 10 states and had increased odds of ICU admission and in-hospital death compared with nonimmunocompromised patients, irrespective of vaccination status. What are the implications for public health practice? Known multilayered prevention measures, including nonpharmaceutical interventions, up-to-date COVID-19 vaccination, and therapeutics, can prevent hospitalization and subsequent severe COVID-19 outcomes among immunocompromised persons.
While most often transient, brachial plexus birth injury can cause permanent neurologic injury. The major risk factors for brachial plexus birth injury are fetal macrosomia and shoulder dystocia. The ...degree of injury to the brachial plexus should be determined in the neonatal nursery, as those infants with the most severe injury--root avulsion--should be referred early for surgical evaluation so that microsurgical repair of the plexus can occur by 3 months of life. Microsurgical repair options include nerve grafts and nerve transfers. All children with brachial plexus birth injury require ongoing physical and occupational therapy and close follow-up to monitor progress.
Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential ...of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.
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•enSERT—a highly efficient CRISPR/Cas9-mediated site-specific transgenic mouse assay•In vivo assessment of all rare variants linked to polydactyly in a human enhancer•In vivo testing showed normal enhancer activity for 30% of presumed pathogenic variants•Systematic mutagenesis of this human enhancer identifies novel pathogenic variants
Development of a scalable in vivo mouse enhancer-reporter assay and its use to systematically interrogate the canonical human ZRS enhancer, which drives Sonic hedgehog expression in mammalian limb development, broadly illuminates enhancer variant pathogenicity.
Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and ...monocytes.
Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients.
IFN-treated monocytes induced caspase 8-dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments.
Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity. See related commentary by Chow and Dorigo, p. 299.
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation ...of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase ...III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE
and Roadmap Epigenomics
data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
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