Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.

Surge effects and survival to hospital discharge in critical care patients with COVID-19 during the early pandemic: a cohort study.

BACKGROUND: The early months of the COVID-19 pandemic were fraught with much uncertainty and some resource constraint. We assessed the change in survival to hospital discharge over time for intensive care unit patients with COVID-19 during the first 3 months of the pandemic and the presence of any surge effects on patient outcomes. METHODS: Retrospective cohort study using electronic medical record data for all patients with laboratory-confirmed COVID-19 admitted to intensive care units from February 25, 2020, to May 15, 2020, at one of 26 hospitals within an integrated delivery system in the Western USA. Patient demographics, comorbidities, and severity of illness were measured along with medical therapies and hospital outcomes over time. Multivariable logistic regression models were constructed to assess temporal changes in survival to hospital discharge during the study period. RESULTS: Of 620 patients with COVID-19 admitted to the ICU [mean age 63.5 years (SD 15.7) and 69% male], 403 (65%) survived to hospital discharge and 217 (35%) died in the hospital. Survival to hospital discharge increased over time, from 60.0% in the first 2 weeks of the study period to 67.6% in the last 2 weeks. In a multivariable logistic regression analysis, the risk-adjusted odds of survival to hospital discharge increased over time (biweekly change, adjusted odds ratio [aOR] 1.22, 95% CI 1.04-1.40, P = 0.02). Additionally, an a priori-defined explanatory model showed that after adjusting for both hospital occupancy and percent hospital capacity by COVID-19-positive individuals and persons under investigation (PUI), the temporal trend in risk-adjusted patient survival to hospital discharge remained the same (biweekly change, aOR 1.18, 95% CI 1.00-1.38, P = 0.04). The presence of greater rates of COVID-19 positive/PUI as a percentage of hospital capacity was, however, significantly and inversely associated with survival to hospital discharge (aOR 0.95, 95% CI 0.92-0.98, P < 0.01). CONCLUSIONS: During the early COVID-19 pandemic, risk-adjusted survival to hospital discharge increased over time for critical care patients. An association was also seen between a greater COVID-19-positive/PUI percentage of hospital capacity and a lower survival rate to hospital discharge.

Epidemiologic features of a large hepatitis C cohort evaluated in a major health system in the western United States.

INTRODUCTION AND AIM: Real-world epidemiologic data to guide hepatitis C virus (HCV)-related public health initiatives are lacking. The aim of this study was to describe the prevalence and epidemiological characteristics of a large cohort of patients with an HCV diagnosis evaluated in one of the largest health systems in the United States. MATERIALS AND METHODS: De-identified demographic and clinical data were extracted from the electronic health record for patients actively followed within the Providence Health & Services health care system. Rates of HCV prevalence and co-morbid illnesses among HCV-infected patients were determined. RESULTS: Among 2,735,511 active patients, 23,492 (0.86%) were found to have evidence of HCV infection, the majority of which were Caucasian (78.2%) and born between the years 1945 and 1965 (68.3%). In comparison to Caucasians, higher rates of HCV infection were found among Native Americans (2.5% vs. 0.95%, p<0.001). Compared to HCV-negative patients, a greater proportion of HCV-positive patients had diabetes mellitus (18.7 vs. 8.9%, p<0.0001), chronic kidney disease (4.4 vs. 1.8%, p<0.0001), end-stage renal disease necessitating hemodialysis (2.6 vs. 0.6%, p<0.0001), and HIV co-infection (2.4 vs. 0.2, p<0.0001). Nearly two-thirds (62.1%) of HCV patients had government-sponsored insurance, and 93.0% of treated patients resided in urban settings. CONCLUSION: The prevalence of HCV infection in this large health care system serving the Pacific Northwest, Alaska, and California was lower than prior population-based estimates and may reflect real-world prevalence rates among patients not selected for risk-based screening. Native Americans are disproportionately affected by HCV and may warrant targeted screening.

Variation in tracheal reintubations among patients undergoing cardiac surgery across Washington state hospitals.

OBJECTIVES: The objectives of this study were to examine the variation in reintubations across Washington state hospitals that perform cardiac surgery, and explore hospital and patient characteristics associated with variation in reintubation. DESIGN: Retrospective cohort study. SETTING: All nonfederal hospitals performing cardiac surgery in Washington state. PARTICIPANTS: A total of 15,103 patients undergoing coronary artery bypass grafting or valvular surgery between January 1, 2008 and September 30, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient and hospital characteristics were compared between hospitals that had a reintubation frequency ≥5% or<5%. Multivariate logistic regression was used to compare the odds of reintubation across the hospitals. The authors tested for heterogeneity of odds of reintubation across hospitals by performing a likelihood ratio test on the hospital factor. After adjusting for patient-level characteristics and procedure type, significant heterogeneity in reintubations across hospitals was present (p = 0.005). This exploratory analyses suggested that hospitals with lower reintubations were more likely to have more acute care days and teaching intensive care units (ICU). CONCLUSIONS: After accounting for patient and procedure characteristics, significant heterogeneity in the relative odds of requiring reintubation was present across 16 nonfederal hospitals performing cardiac surgery in Washington state. The findings suggested that greater hospital volume and ICU teaching status were associated with fewer reintubations.

Community differentiation and kinship among Europe's first farmers.

Community differentiation is a fundamental topic of the social sciences, and its prehistoric origins in Europe are typically assumed to lie among the complex, densely populated societies that developed millennia after their Neolithic predecessors. Here we present the earliest, statistically significant evidence for such differentiation among the first farmers of Neolithic Europe. By using strontium isotopic data from more than 300 early Neolithic human skeletons, we find significantly less variance in geographic signatures among males than we find among females, and less variance among burials with ground stone adzes than burials without such adzes. From this, in context with other available evidence, we infer differential land use in early Neolithic central Europe within a patrilocal kinship system.

Sepsis Order Set Use Associated With Increased Care Value.

BACKGROUND: Sepsis is common and expensive, and evidence suggests that sepsis order sets may help to improve care. Very incomplete evidence exists regarding the effects of sepsis order sets on the value of care produced by hospitals or the societal costs of sepsis care. RESEARCH QUESTION: In patients hospitalized for sepsis, is the receipt a of a sepsis order set vs no order set associated with improved value of care, defined as decreased hospital mortality, decreased hospital direct variable costs, and decreased societal spending on hospitalizations? STUDY DESIGN AND METHODS: This retrospective cohort study included patients discharged with sepsis International Classification of Diseases, Tenth Revision, codes over 2 years from a large integrated delivery system. Using a propensity score, sepsis order set users were matched to nonusers to study the association between sepsis order set use and the value of care from the hospital and societal perspective. The association between order set receipt and hospital mortality, direct variable cost, and hospital revenue also were examined in a priori defined subgroups of sepsis severity and hospital mortality. RESULTS: The study included 97,249 patients, with 52,793 patients (54%) receiving the sepsis order set. The propensity score match analysis included 55,542 patients, with 27,771 patients in each group. Recipients of the sepsis order set showed a 3.3% lower hospital mortality rate and a $1,487 lower median direct variable total cost (P < .01 for both). Median payer-neutral reimbursement (PNR), a proxy for hospital revenue and thus societal costs, was $465 lower for sepsis order set users (P < .01). Receipt of the sepsis order set was associated with a $1,022 increase in contribution margin, the difference between direct variable costs and PNR per patient. INTERPRETATION: Receipt of the sepsis order set was associated with improved value of care, from both a hospital and societal perspective.

A greater analgesia, sedation, delirium order set quality score is associated with a decreased duration of mechanical ventilation in cardiovascular surgery patients.

OBJECTIVE: Protocols and order sets for the delivery of analgesia, sedation, and delirium care of the critically ill, mechanically ventilated patient have been shown to improve outcomes but are not uniform in hospitals across geographic areas. The extent to which greater order set quality is associated with improved patient outcomes is not known. We hypothesized that cardiac surgery patients cared for at hospitals with a greater analgesia, sedation, and delirium order set quality score (more guideline-concordant order sets) would have a shorter average duration of mechanical ventilation. DESIGN: Retrospective cohort study. SETTING: All Washington State non-federal hospitals providing cardiac surgery. PATIENTS: All mechanically ventilated cardiac surgery patients from January 1, 2008, until September 30, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a multivariable linear regression model to assess the relationship between a hospital's pain, agitation and delirium order set quality, as assessed by an expert-validated order set quality score, and the average duration of mechanical ventilation of its cardiac surgery patients, independent of other hospital and patient factors. A total of 19,561 patients underwent cardiac surgery at 16 Washington state hospitals during the study period. The order set quality scores ranged from 4 to 19 with a mean of 11.8 ± 4.5. The mean duration of mechanical ventilation was 27.0 ± 196.6 hours. In the multivariable model, independent of other patient and hospital factors, a 1-point increase in the order set quality score was associated with a 3.3 ± 0.9 hour (p < 0.01) decrease in average duration of mechanical ventilation. CONCLUSIONS: Cardiac surgery hospitals with more guideline-adherent analgesia, sedation, and delirium order sets have patients with shorter mean durations of mechanical ventilation than hospitals with lower order set quality scores.

Order Set Usage is Associated With Lower Hospital Mortality in Patients With Sepsis.

The Surviving Sepsis Campaign recommends standard operating procedures for patients with sepsis. Real-world evidence about sepsis order set implementation is limited. OBJECTIVES: To estimate the effect of sepsis order set usage on hospital mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Fifty-four acute care hospitals in the United States from December 1, 2020 to November 30, 2022 involving 104,662 patients hospitalized for sepsis. MAIN OUTCOMES AND MEASURES: Hospital mortality. RESULTS: The sepsis order set was used in 58,091 (55.5%) patients with sepsis. Initial mean sequential organ failure assessment score was 0.3 lower in patients for whom the order set was used than in those for whom it was not used (2.9 sd [2.8] vs 3.2 [3.1], p < 0.01). In bivariate analysis, hospital mortality was 6.3% lower in patients for whom the sepsis order set was used (9.7% vs 16.0%, p < 0.01), median time from emergency department triage to antibiotics was 54 minutes less (125 interquartile range [IQR, 68-221] vs 179 [98-379], p < 0.01), and median total time hypotensive was 2.1 hours less (5.5 IQR [2.0-15.0] vs 7.6 [2.5-21.8], p < 0.01) and septic shock was 3.2% less common (22.0% vs 25.4%, p < 0.01). Order set use was associated with 1.1 fewer median days of hospitalization (4.9 [2.8-9.0] vs 6.0 [3.2-12.1], p < 0.01), and 6.6% more patients discharged to home (61.4% vs 54.8%, p < 0.01). In the multivariable model, sepsis order set use was independently associated with lower hospital mortality (odds ratio 0.70; 95% CI, 0.66-0.73). CONCLUSIONS AND RELEVANCE: In a cohort of patients hospitalized with sepsis, order set use was independently associated with lower hospital mortality. Order sets can impact large-scale quality improvement efforts.

Association between hospital volume and network membership and an analgesia, sedation and delirium order set quality score: a cohort study.

INTRODUCTION: Protocols for the delivery of analgesia, sedation and delirium care of the critically ill, mechanically ventilated patient have been shown to improve outcomes but are not uniformly used. The extent to which elements of analgesia, sedation and delirium guidelines are incorporated into order sets at hospitals across a geographic area is not known. We hypothesized that both greater hospital volume and membership in a hospital network are associated with greater adherence of order sets to sedation guidelines. METHODS: Sedation order sets from all nonfederal hospitals without pediatric designation in Washington State that provided ongoing care to mechanically ventilated patients were collected and their content systematically abstracted. Hospital data were collected from Washington State sources and interviews with ICU leadership in each hospital. An expert-validated score of order set quality was created based on the 2002 four-society guidelines. Clustered multivariable linear regression was used to assess the relationship between hospital characteristics and the order set quality score. RESULTS: Fifty-one Washington State hospitals met the inclusion criteria and all provided order sets. Based on expert consensus, 21 elements were included in the analgesia, sedation and delirium order set quality score. Each element was equally weighted and contributed one point to the score. Hospital order set quality scores ranged from 0 to 19 (median = 8, interquartile range 6 to 14). In multivariable analysis, a greater number of acute care days (P = 0.01) and membership in a larger hospital network (P = 0.01) were independently associated with a greater quality score. CONCLUSIONS: Hospital volume and membership in a larger hospital network were independently associated with a higher quality score for ICU analgesia, sedation and delirium order sets. Further research is needed to determine whether greater order-set quality is associated with improved outcomes in the critically ill. The development of critical care networks might be one strategy to improve order set quality scores.

Plant Virus and Virus-like Disease Threats to Australia's North Targeted by the Northern Australia Quarantine Strategy.

The Northern Australia Quarantine Strategy (NAQS) is a biosecurity initiative operated by the Australian federal government's Department of Agriculture, Water and the Environment (DAWE). It is unique worldwide because it deals specifically with the potential arrival via unregulated pathways of exotic threats from overseas in a vast and sparsely populated region. It aims to protect the nation's animal- and plant-based production industries, as well as the environment, from incursions of organisms from countries that lie immediately to the north. These are diseases, pests, and weeds present in these countries that are currently either absent from, or under active containment in, Australia and may arrive by natural or human-assisted means. This review article focuses on the plant viruses and virus-like diseases that are most highly targeted by the NAQS program. It presents eight pathogen species/group entries in the NAQS A list of target pathogens, providing an overview of the historical and current situation, and collates some new data obtained from surveillance activities conducted in northern Australia and collaborative work overseas.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories.

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8 + and CD4 + T cells, and cytotoxic CD4 + T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

Quality control measures for placental sample purity in DNA methylation array analyses.

The purity of tissue samples can affect the accuracy and utility of DNA methylation array analyses. This is particularly important for the placenta which is globally hypomethylated compared to other tissues. Placental villous tissue from early pregnancy terminations can be difficult to separate from non-villous tissue, resulting in potentially inaccurate results. We used several methods to identify mixed placenta samples using DNA methylation array datasets from our laboratory and those contained in the NCBI GEO database, highlighting the importance of determining sample purity during quality control processes.

Supplementary prescribing in mental health and learning disabilities.

Nurse prescribing in mental health and learning disability services is a new development. The experiences of nine nurses working in mental health and learning disabilities, who formed part of the first cohort in the U.K. to undertake the supplementary nurse prescribing course, are described. Experiences of the course and implementation of supplementary prescribing in practice are discussed. The attitudes of nurses, other health professionals and patients to nurse prescribing are also explored.

Hospital-level factors associated with report of physical activity in patients on mechanical ventilation across Washington State.

RATIONALE: Use of physical and/or occupational therapy in the intensive care unit (ICU) is safe, feasible, and demonstrates improvements in functional status with early administration. Access to physical and/or occupational therapy in the ICU is variable, with little known regarding its use in community ICUs. OBJECTIVES: Determine what proportion of hospitals across Washington State report use of physical activity in mechanically ventilated patients and investigate process of care factors associated with reported activity delivery. METHODS: Cross-sectional telephone interview survey study of nurse managers in hospitals caring for patients on mechanical ventilation across Washington State in 2013. Survey responses were linked with hospital-level data available in the Washington State Department of Health Comprehensive Hospital Abstract Reporting System database. Chi-square testing was used to explore unadjusted associations between potential process of care factors and report on activity delivery. Two multivariable logistic regression models were developed to explore the association between presence of a mobility protocol and report on delivery of activity. MEASUREMENTS AND MAIN RESULTS: We identified 54 hospitals caring for patients on mechanical ventilation; 47 participated in the survey (response rate, 85.5%). Nurse managers from 36 (76.6%) hospitals reported use of physical activity in patients on mechanical ventilation, with 22 (46.8%) reporting use of high-level physical activity (transferring to chair, standing or ambulating) and 24 (51.1%) reporting use in high-severity patients (patients requiring mechanical ventilation and/or vasopressors). Presence of a written ICU activity protocol (odds ratio [OR], 5.54; 95% confidence interval [CI], 1.60-19.18; P = 0.006), hospital volume (OR, 5.33; 95% CI, 1.54-18.48; P = 0.008), and academic affiliation (OR, 4.40; 95% CI, 1.23-15.63; P = 0.02) were associated with report of higher level activity. Presence of a written ICU activity protocol (OR, 6.00; 95% CI, 1.69-21.14; P = 0.005) and academic affiliation (OR, 4.50; 95% CI, 1.21-16.46; P = 0.02) were associated with report of delivery of physical activity to high-severity patients. CONCLUSIONS: Nurse managers at three-fourths (76.6%) of eligible hospitals across Washington State reported use of physical activity in patients on mechanical ventilation. Hospital-level factors including hospital volume, academic affiliation, and presence of a mobility protocol were associated with report of higher level activity and delivery of activity to high-severity patients.

A multifaceted hospitalist quality improvement intervention: Decreased frequency of common labs.

PURPOSE: Common labs such as a daily complete blood count or a daily basic metabolic panel represent possible waste and have been targeted by professional societies and the Choosing Wisely campaign for critical evaluation. We undertook a multifaceted quality-improvement (QI) intervention in a large community hospitalist group to decrease unnecessary common labs. METHODS: The QI intervention was composed of academic detailing, audit and feedback, and transparent reporting of the frequency with which common labs were ordered as daily within the hospitalist group. We performed a pre-post analysis, comparing a cohort of patients during the 10-month baseline period before the QI intervention and the 7-month intervention period. Demographic and clinical data were collected from the electronic medical record. The primary endpoint was number of common labs ordered per patient-day as estimated by a clustered multivariable linear regression model clustering by ordering hospitalist. Secondary endpoints included length of stay, hospital mortality, 30-day readmission, blood transfusion, amount of blood transfused, and laboratory cost per patient. RESULTS: The baseline (n = 7824) and intervention (n = 5759) cohorts were similar in their demographics, though the distribution of primary discharge diagnosis-related groups differed. At baseline, a mean of 2.06 (standard deviation 1.40) common labs were ordered per patient-day. Adjusting for age, sex, and principle discharge diagnosis, the number of common labs ordered per patient-day decreased by 0.22 (10.7%) during the intervention period compared to baseline (95% confidence interval [CI], 0.34 to 0.11; P < 0.01). There were nonsignificant reductions in hospital mortality in the intervention period compared to baseline (2.2% vs 1.8%, P = 0.1) as well as volume of blood transfused in patients who received a transfusion (127.2 mL decrease; 95% CI, -257.9 to 3.6; P = 0.06). No effect was seen on length of stay or readmission rate. The intervention decreased hospital direct costs by an estimated $16.19 per admission or $151,682 annualized (95% CI, $119,746 to $187,618). CONCLUSION: Implementation of a multifaceted QI intervention within a community-based hospitalist group was associated with a significant, but modest, decrease in the number of ordered lab tests and hospital costs. No effect was seen on hospital length of stay, mortality, or readmission rate. This intervention suggests that a community-based hospitalist QI intervention focused on daily labs can be effective in safely reducing healthcare waste without compromising quality of care.

Improved analgesia, sedation, and delirium protocol associated with decreased duration of delirium and mechanical ventilation.

RATIONALE: Introduction of sedation protocols has been associated with improved patient outcomes. It is not known if an update to an existing high-quality sedation protocol, featuring increased patient assessment and reduced benzodiazepine exposure, is associated with improved patient process and outcome quality metrics. METHODS: This was an observational before (n = 703) and after (n = 780) cohort study of mechanically ventilated patients in a 24-bed trauma-surgical intensive care unit (ICU) from 2009 to 2011. The three main protocol updates were: (1) requirement to document Richmond Agitation Sedation Scale (RASS) scores every 4 hours, (2) requirement to document Confusion Assessment Method-ICU (CAM ICU) twice daily, and (3) systematic, protocolized deescalation of excess sedation. Multivariable linear regression was used for the primary analysis. The primary outcome was the duration of mechanical ventilation. Prespecified secondary endpoints included days of delirium; the frequency of patient assessment with the RASS and CAM-ICU instruments; benzodiazepine dosing; durations of mechanical ventilation, ICU stay, and hospitalization; and hospital mortality and ventilator associated pneumonia rate. RESULTS: Patients in the updated protocol cohort had 1.22 more RASS assessments per day (5.38 vs. 4.16; 95% confidence interval [CI], 1.05-1.39; P < 0.01) and 1.15 more CAM-ICU assessments per day (1.49 vs. 0.35; 95% CI, 1.08-1.21; P < 0.01) than the baseline cohort. The mean hourly benzodiazepine dose decreased by 34.8% (0.08 mg lorazepam equivalents/h; 0.15 vs. 0.23; P < 0.01). In the multivariable model, the median duration of mechanical ventilation decreased by 17.6% (95% CI, 0.6-31.7%; P = 0.04). The overall odds ratio of delirium was 0.67 (95% CI, 0.49-0.91; P = 0.01) comparing updated versus baseline cohort. A 12.4% reduction in median duration of ICU stay (95% CI, 0.5-22.8%; P = 0.04) and a 14.0% reduction in median duration of hospitalization (95% CI, 2.0-24.5%; P = 0.02) were also seen. No significant association with mortality (odds ratio, 1.18; 95% CI, 0.80-1.76; P = 0.40) was seen. CONCLUSIONS: Implementation of an updated ICU analgesia, sedation, and delirium protocol was associated with an increase in RASS and CAM-ICU assessment and documentation; reduced hourly benzodiazepine dose; and decreased delirium and median durations of mechanical ventilation, ICU stay, and hospitalization.