Detecting Sepsis Using Sepsis-Related Organ Failure Assessment (SOFA) and an Electronic Sepsis Prompt in Intensive Care Unit Adult Patients

Sepsis is an elusive and costly syndrome that is one of the leading causes of death globally. Annually, there are approximately 19 million cases of sepsis that result in more than 5 million deaths. The Agency for Healthcare Research and Quality (AHRQ) ranked sepsis as the most expensive condition ($23.7 billion) for patients treated in hospitals in the United States (U.S.). Nurses are critical in the early identification of sepsis and implementation of therapeutic interventions known as the “sepsis bundle”. Previously, sepsis was described as a systemic, pro-inflammatory response to an infection. Sepsis was defined as two or more systemic inflammatory response syndrome (SIRS) criteria with a suspected infection, severe sepsis was defined as sepsis with organ failure and septic shock was defined as severe sepsis with shock. For several decades SIRS criteria with organ failure criteria have been used to develop measurement systems for detection of sepsis. A recent study comparing SIRS criteria to the sepsis-related organ failure assessment (SOFA) score demonstrated that SOFA had greater prognostic accuracy of mortality in patients with an infection than SIRS. This led to sepsis definition changes in 2016. The term “severe sepsis” was dropped and sepsis was defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection leading to tissue injury and organ failure. Many clinicians were concerned that this new definition might lead to late detection of sepsis. What was unknown was how well SIRS with organ failure criteria compared with SOFA in detection of sepsis. Many clinicians in the U.S. working in a TeleICU had been using SIRS with organ failure criteria to support early identification of sepsis. Using human factors science concepts, their practice was studied and an electronic sepsis alert (sepsis prompt) was developed. Thus, the overall objective of this dissertation was to conduct a retrospective study using a large U.S. data repository to determine if an electronic prompt, that uses SIRS and organ failure (OF) criteria, can detect sepsis. Another objective of this study was to determine the prognostic accuracy of the SOFA score and the sepsis prompt in discriminating in-hospital mortality among patients with sepsis in the intensive care unit. Among 2,020,489 patients admitted to ICUs associated with a TeleICU from January 1, 2010, to December 31, 2015, at 459 hospitals throughout the U.S., we identified 912,509 (45%) eligible patients at 183 hospitals. We compared the performance of the SOFA score and sepsis prompt criteria in detecting sepsis. Of those in the primary cohort, a secondary cohort was derived based on presence of sepsis resulting 186,870 (20.5%) patients. To assess performances of the SOFA score and the sepsis prompt (a Fuzzy Logic SIRS and OF algorithm) to detect sepsis, we calculated diagnostic performance of an increase in the SOFA score of 2 or more and criteria met for the Fuzzy Logic SIRS and OF algorithm. For predictive validity, training of baseline risk models was performed on training sets with prediction and performance analytics completed on test sets for each cohort for the outcomes of mortality and sepsis. Results were expressed as the fold change in outcome over deciles of baseline risk of death or risk of sepsis, area under the receiver operating characteristic curve (AUROC), and sensitivity, specificity, and negative and positive predictive values. In the primary cohort (912,509) there were 86,219 (9.4%) who did not survive their hospital stay and 186,870 (20.5%) with suspected sepsis of whom 34,617 (18.5%) did not survive hospitalization. The Fuzzy Logic SIRS/OF (crude AUROC 0.67, 99% CI: 0.66-0.67 and adjusted AUROC 0.77, 99% CI: 0.77-0.77) outperformed SOFA (crude AUROC 0.61, 99% CI: 0.61-0.61 and adjusted AUROC 0.74, 99% CI: 0.74-0.74) in discrimination of sepsis in both crude and adjusted AUROC (in-between differences AUROC 0.06; z-value 49.06 and AUROC 0.03; z-value 36.22, respectively). In the primary cohort, Fuzzy Logic SIRS/OF (crude AUROC 0.67, 99% CI: 0.67-0.68 and adjusted AUROC 0.78, 99% CI: 0.77-0.78) outperformed SOFA (crude AUROC 0.64, 99% CI: 0.64-0.64 and adjusted AUROC 0.76, 99% CI: 0.76-0.76) in prognostic accuracy of mortality in both crude and adjusted AUROC (in-between differences AUROC 0.03; z-value 24.68 and AUROC 0.02; z-value 14.74, respectively). In the secondary cohort, Fuzzy Logic SIRS/OF (crude AUROC 0.57, 99% CI: 0.57-0.58 and adjusted AUROC 0.69, 99% CI: 0.68-0.70) outperformed SOFA (crude AUROC 0.56, 99% CI: 0.56-0.56 and adjusted AUROC 0.68, 99% CI: 0.67-0.68) in prognostic accuracy of mortality in both crude and adjusted AUROC (in-between differences AUROC 0.01; z-value 6.86 and AUROC 0.01; z-value 7.53, respectively). The results of this study demonstrated that among adult ICU patients, the predictive validity for sepsis and in-hospital mortality of a complex algorithm based on Fuzzy Logic applied to expanded SIRS criteria with organ failure criteria was better than SOFA for detection of sepsis and for prognostic accuracy of mortality. The findings of this study support the use of a computer-enhanced algorithm that includes a combination of expanded SIRS with organ failure criteria as a tool to assist nurses and healthcare providers in early identification of sepsis

Overview of recent TJ-II stellarator results

The main results obtained in the TJ-II stellarator in the last two years are reported. The most important topics investigated have been modelling and validation of impurity transport, validation of gyrokinetic simulations, turbulence characterisation, effect of magnetic configuration on transport, fuelling with pellet injection, fast particles and liquid metal plasma facing components. As regards impurity transport research, a number of working lines exploring several recently discovered effects have been developed: the effect of tangential drifts on stellarator neoclassical transport, the impurity flux driven by electric fields tangent to magnetic surfaces and attempts of experimental validation with Doppler reflectometry of the variation of the radial electric field on the flux surface. Concerning gyrokinetic simulations, two validation activities have been performed, the comparison with measurements of zonal flow relaxation in pellet-induced fast transients and the comparison with experimental poloidal variation of fluctuations amplitude. The impact of radial electric fields on turbulence spreading in the edge and scrape-off layer has been also experimentally characterized using a 2D Langmuir probe array. Another remarkable piece of work has been the investigation of the radial propagation of small temperature perturbations using transfer entropy. Research on the physics and modelling of plasma core fuelling with pellet and tracer-encapsulated solid-pellet injection has produced also relevant results. Neutral beam injection driven Alfvénic activity and its possible control by electron cyclotron current drive has been examined as well in TJ-II. Finally, recent results on alternative plasma facing components based on liquid metals are also presentedThis work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under Grant Agreement No. 633053. It has been partially funded by the Ministerio de Ciencia, Inovación y Universidades of Spain under projects ENE2013-48109-P, ENE2015-70142-P and FIS2017-88892-P. It has also received funds from the Spanish Government via mobility grant PRX17/00425. The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona S.C. It has been supported as well by The Science and Technology Center in Ukraine (STCU), Project P-507F

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Development and evaluation of a machine learning-based in-hospital COVID-19 disease outcome predictor (CODOP): A multicontinental retrospective study

New SARS-CoV-2 variants, breakthrough infections, waning immunity, and sub-optimal vaccination rates account for surges of hospitalizations and deaths. There is an urgent need for clinically valuable and generalizable triage tools assisting the allocation of hospital resources, particularly in resource-limited countries. We developed and validate CODOP, a machine learning-based tool for predicting the clinical outcome of hospitalized COVID-19 patients. CODOP was trained, tested and validated with six cohorts encompassing 29223 COVID-19 patients from more than 150 hospitals in Spain, the USA and Latin America during 2020-22. CODOP uses 12 clinical parameters commonly measured at hospital admission for reaching high discriminative ability up to 9 days before clinical resolution (AUROC: 0.90-0.96), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. Furthermore, CODOP maintains its predictive ability independently of the virus variant and the vaccination status. To reckon with the fluctuating pressure levels in hospitals during the pandemic, we offer two online CODOP calculators, suited for undertriage or overtriage scenarios, validated with a cohort of patients from 42 hospitals in three Latin American countries (78-100% sensitivity and 89-97% specificity). The performance of CODOP in heterogeneous and geographically disperse patient cohorts and the easiness of use strongly suggest its clinical utility, particularly in resource-limited countries

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Survey of Nurses\u27 Experiences Applying The Joint Commission\u27s Medication Management Titration Standards

BACKGROUND: Critical care nurses titrate continuous infusions of medications to achieve clinical end points. In 2017, The Joint Commission (TJC) placed restrictions on titration practice, decreasing nurses\u27 autonomous decision-making. OBJECTIVES: To describe the practice and perceptions of nurses regarding the 2017 TJC accreditation/regulatory standards for titration of continuous medication infusions. METHODS: A survey of nurses\u27 experiences titrating continuous medication infusions was developed, validated, and distributed electronically to members of the American Association of Critical-Care Nurses. RESULTS: The content validity index for the survey was 1.0 for relevance and 0.95 for clarity. A total of 781 nurses completed the survey; 625 (80%) perceived titration standards to cause delays in patient care, and 726 (93%) experienced moral distress (mean [SD], 4.97 [2.67]; scale, 0-10). Among respondents, 33% could not comply with titration orders, 68% reported suboptimal care resulting from pressure to comply with orders, 70% deviated from orders to meet patient needs, and 84% requested revised orders to ensure compliance. Suboptimal care and delays in care significantly and strongly (regression coefficients \u3e /=0.69) predicted moral distress. CONCLUSIONS: Critical care nurses perceive TJC medication titration standards to adversely impact patient care and contribute to moral distress. The improved 2020 updates to the standards do not address delays and inability to comply with orders, leading to moral distress. Advocacy is indicated in order to mitigate unintended consequences of TJC medication management titration standards

Describing advanced practice provider roles within critical care teams with Tele-ICUs: Exemplars from seven US health systems

Telehealth is an acknowledged strategy to meet patient healthcare needs. In critical care settings, Tele-ICU\u27s are expanding to deliver clinical services across a diverse spectrum of critically ill patients. The expansion of telehealth provides increased opportunities for advanced practice providers including advanced practice nurses and physician assistants; however, limited information on roles and models of care for advanced practice providers in telehealth exist. This article reviews current and evolving roles for advanced practice providers in telehealth in acute and critical care settings across 7 healthcare systems in the United States. The health system exemplars described in this article identify the important role of advanced practice providers in providing patient care oversight and in improving outcomes for acute and critically ill patients. As telehealth continues to expand, additional opportunities will lead to novel roles for advanced practice providers in the field of telehealth to assist with patient care management for subacute, acute, and critically ill patients