Three Epochs of Artificial Intelligence in Health Care.

Importance: Interest in artificial intelligence (AI) has reached an all-time high, and health care leaders across the ecosystem are faced with questions about where, when, and how to deploy AI and how to understand its risks, problems, and possibilities. Observations: While AI as a concept has existed since the 1950s, all AI is not the same. Capabilities and risks of various kinds of AI differ markedly, and on examination 3 epochs of AI emerge. AI 1.0 includes symbolic AI, which attempts to encode human knowledge into computational rules, as well as probabilistic models. The era of AI 2.0 began with deep learning, in which models learn from examples labeled with ground truth. This era brought about many advances both in people's daily lives and in health care. Deep learning models are task-specific, meaning they do one thing at a time, and they primarily focus on classification and prediction. AI 3.0 is the era of foundation models and generative AI. Models in AI 3.0 have fundamentally new (and potentially transformative) capabilities, as well as new kinds of risks, such as hallucinations. These models can do many different kinds of tasks without being retrained on a new dataset. For example, a simple text instruction will change the model's behavior. Prompts such as "Write this note for a specialist consultant" and "Write this note for the patient's mother" will produce markedly different content. Conclusions and Relevance: Foundation models and generative AI represent a major revolution in AI's capabilities, ffering tremendous potential to improve care. Health care leaders are making decisions about AI today. While any heuristic omits details and loses nuance, the framework of AI 1.0, 2.0, and 3.0 may be helpful to decision-makers because each epoch has fundamentally different capabilities and risks.

A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease.

A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial.

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies.

BACKGROUND: Janus kinase (JAK)-mediated cytokine signalling contributes to local and systemic inflammation in hidradenitis suppurativa (HS). OBJECTIVES: To describe the safety and efficacy results from two multicentre phase II trials of the JAK1 inhibitor INCB054707 in patients with moderate-to-severe HS. METHODS: Patients received open-label INCB054707 15 mg once daily (QD; Study 1) or were randomized to INCB054707 30, 60 or 90 mg QD or placebo (3 : 1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18-75 years and had moderate-to-severe HS (Hurley stage II/III disease), lesions present in at least two anatomical locations, and a total abscess and inflammatory nodule count ≥ 3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures. RESULTS: Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8; placebo, n = 9). Overall, 70% of patients in Study 1 and 81% of patients receiving INCB054707 in Study 2 experienced at least one treatment-emergent adverse event; 30% and 42% of patients, respectively, had at least one treatment-related adverse event. Among the evaluable patients, three (43%) in Study 1 and 17 (65% overall: 30 mg, 56%; 60 mg, 56%; 90 mg, 88%) receiving INCB054707 vs. 4 patients (57%) receiving placebo in Study 2 achieved HiSCR at week 8. CONCLUSIONS: INCB054707 was well tolerated, with responses observed in patients with moderate-to-severe HS. The safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS. The studies are registered on ClinicalTrials.gov (NCT03569371 and NCT03607487).

Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.

BACKGROUND: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation and reduced quality of life. There is no approved treatment for vitiligo repigmentation and current off-label therapies have limited efficacy, emphasising the need for improved treatment options. We investigated the therapeutic potential of ruxolitinib cream in patients with vitiligo and report the efficacy and safety results up to 52 weeks of double-blind treatment. METHODS: We did a multicentre, randomised, double-blind, phase 2 study for adult patients with vitiligo in 26 US hospitals and medical centres in 18 states. Patients with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA were randomly assigned (1:1:1:1:1) by use of an interactive response technology system to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle (control group) twice daily on lesions constituting 20% or less of their total BSA for 24 weeks. Patients in the control group in addition to patients in the 0·15% once daily group who did not show a 25% or higher improvement from baseline in facial Vitiligo Area Scoring Index (F-VASI) at week 24 were re-randomised to one of three higher ruxolitinib cream doses (0·5% once daily, 1·5% once daily, 1·5% twice daily). Patients in the 0·5% once daily, 1·5% once daily, or 1·5% twice daily groups remained at their original dose up to week 52. Patients, investigators, and the study sponsor (except members of the interim analysis and primary endpoint analysis data monitoring teams) remained masked to treatment assignment throughout the study. The primary endpoint was the proportion of patients achieving a 50% or higher improvement from baseline in F-VASI (F-VASI50) at week 24, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03099304. FINDINGS: Between June 7, 2017, and March 21, 2018, 205 patients were screened for eligibility, 48 were excluded and 157 patients (mean age, 48·3 years [SD 12·9]; 73 [46%] male and 84 [54%] female) were randomly assigned to either an intervention group or the control group. 32 (20%) of 157 were assigned to the control group, 31 (20%) to the 0·15% once daily group, 31 (20%) to the 0·5% once daily group, 30 (19%) to the 1·5% once daily group, and 33 (21%) to the 1·5% twice daily group. F-VASI50 at week 24 was reached by significantly more patients given ruxolitinib cream at 1·5% twice daily (15 [45%] of 33) and 1·5% once daily (15 [50%] of 30) than were treated with vehicle (one [3%] of 32). Four patients had serious treatment-emergent adverse events (one patient in the 1·5% twice daily group developed subdural haematoma; one patient in the 1·5% once daily group had a seizure; one patient in the 0·5% once daily group had coronary artery occlusion; and one patient in the 0·5% once daily group had oesophageal achalasia), all of which were unrelated to study treatment. Application site pruritus was the most common treatment-related adverse event among patients given ruxolitinib cream (one [3%] of 33 in the 1·5% twice daily group; three [10%] of 30 in the 1·5% once daily group; three [10%] of 31 in the 0·5% once daily group; and six [19%] of 31 in the 0·15% once daily group)with three [9%] of 32 patients showing application site pruritis in the control group. Acne was noted as a treatment-related adverse event in 13 (10%) of 125 patients who received ruxolitinib cream and one (3%) of 32 patients who received vehicle cream. All treatment-related adverse events were mild or moderate in severity and similar across treatment groups. INTERPRETATION: Treatment with ruxolitinib cream was associated with substantial repigmentation of vitiligo lesions up to 52 weeks of treatment, and all doses were well tolerated. These data suggest that ruxolitinib cream might be an effective treatment option for patients with vitiligo. FUNDING: Incyte.

Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream.

BACKGROUND: Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disorder. Ruxolitinib, a selective inhibitor of Janus kinase 1 and Janus kinase 2, potently suppresses cytokine signaling involved in AD pathogenesis. OBJECTIVE: We sought to evaluate the efficacy and safety of ruxolitinib (RUX) cream in adults with AD. METHODS: In this phase 2 study (NCT03011892), 307 adult patients with AD, an Investigator's Global Assessment score of 2 or 3 (mild or moderate), and 3% to 20% affected body surface area were equally randomized for 8 weeks of double-blind treatment to RUX (1.5% twice daily [BID], 1.5% once daily [QD], 0.5% QD, 0.15% QD), vehicle, or triamcinolone cream (0.1% BID for 4 weeks, then vehicle for 4 weeks). Subsequently, patients could apply 1.5% RUX BID for 4 additional weeks of open-label treatment. The primary end point was the comparison between 1.5% RUX cream BID and vehicle in mean percentage change from baseline in Eczema Area and Severity Index at week 4. RESULTS: All RUX regimens demonstrated therapeutic benefit at week 4; 1.5% BID provided the greatest improvement in Eczema Area and Severity Index (71.6% vs 15.5%; P < .0001) and Investigator's Global Assessment responses (38.0% vs 7.7%; P < .001) versus vehicle. Rapid reductions in the itch numerical rating scale score occurred within 36 hours (1.5% BID vs vehicle, ‒1.8 vs ‒0.2; P < .0001) and were sustained through 12 weeks. Patients who transitioned to 1.5% RUX BID improved in all measures. RUX was not associated with clinically significant application-site reactions. CONCLUSIONS: RUX cream provided rapid and sustained improvements in AD symptoms and was well tolerated.

Interplay between Humoral and CLA+ T Cell Response against Candida albicans in Psoriasis.

Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA- cutaneous lymphocyte antigen (CLA)+/- T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA+ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA+ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.

Transcriptomic analysis of hidradenitis suppurativa skin suggests roles for multiple inflammatory pathways in disease pathogenesis.

OBJECTIVE: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with limited treatment options; therefore, the current study investigated the downstream signaling pathways that are differentially expressed in HS subjects and may drive disease pathogenesis. METHODS: The expression of 144 genes was evaluated in the skin of 16 healthy subjects and 34 subjects with mild to severe HS using QuantiGene Plex assay. RESULTS: One hundred and twenty-nine genes were significantly elevated in lesional HS skin as compared to the skin of healthy controls including pro-inflammatory cytokines (IL-1α, IL-6, TNF-α), IL-17-associated cytokines (IL-17A, IL-17F, IL-23A), the IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, IL-24), and IFN family members (IFNA1, IFNB1, IFNG, IL-12B). This corresponded with increased expression of tyrosine kinases (JAK1, JAK3, BTK, SYK) and their downstream signaling partners (STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6). CONCLUSION: These data illustrate the diverse immune activation in lesional HS skin and suggest that deeper interrogation of the disease heterogeneity may reveal unique opportunities for targeted therapies in designated subpopulations.

Customization scenarios for de-identification of clinical notes.

BACKGROUND: Automated machine-learning systems are able to de-identify electronic medical records, including free-text clinical notes. Use of such systems would greatly boost the amount of data available to researchers, yet their deployment has been limited due to uncertainty about their performance when applied to new datasets. OBJECTIVE: We present practical options for clinical note de-identification, assessing performance of machine learning systems ranging from off-the-shelf to fully customized. METHODS: We implement a state-of-the-art machine learning de-identification system, training and testing on pairs of datasets that match the deployment scenarios. We use clinical notes from two i2b2 competition corpora, the Physionet Gold Standard corpus, and parts of the MIMIC-III dataset. RESULTS: Fully customized systems remove 97-99% of personally identifying information. Performance of off-the-shelf systems varies by dataset, with performance mostly above 90%. Providing a small labeled dataset or large unlabeled dataset allows for fine-tuning that improves performance over off-the-shelf systems. CONCLUSION: Health organizations should be aware of the levels of customization available when selecting a de-identification deployment solution, in order to choose the one that best matches their resources and target performance level.

Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.

BACKGROUND: IL-13 has an important role in atopic dermatitis (AD) pathogenesis. Tralokinumab is a fully human mAb that potently and specifically neutralizes IL-13. OBJECTIVE: We sought to evaluate the efficacy and safety of tralokinumab in adults with moderate-to-severe AD. METHODS: In this phase 2b study (NCT02347176), 204 adults were randomized 1:1:1:1 to receive 45, 150, or 300 mg of subcutaneous tralokinumab, or placebo, every 2 weeks for 12 weeks with concomitant topical glucocorticoids. Coprimary end points were change from baseline in Eczema Area Severity Index score and percentage of participants with an Investigator's Global Assessment response (0/1 score and reduction of ≥2 grades from baseline) at week 12. RESULTS: At week 12, 300 mg of tralokinumab significantly improved change from baseline in Eczema Area Severity Index score versus placebo (adjusted mean difference, -4.94; 95% CI, -8.76 to -1.13; P = .01), and a greater percentage of participants achieved an Investigator's Global Assessment response (26.7% vs 11.8%). Greater responses were found in participants with greater concentrations of biomarkers of increased IL-13 activity. Participants treated with 300 mg of tralokinumab demonstrated improvements in SCORAD, Dermatology Life Quality Index, and pruritus numeric rating scale (7-day mean) scores versus placebo. Upper respiratory tract infection was the most frequent treatment-emergent adverse event reported as related to study drug in the placebo (3.9%) and pooled tralokinumab (3.9%) groups. CONCLUSIONS: Tralokinumab treatment was associated with early and sustained improvements in AD symptoms and an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with AD.

The Practice of Respect in the ICU.

Although "respect" and "dignity" are intuitive concepts, little formal work has addressed their systematic application in the ICU setting. After convening a multidisciplinary group of relevant experts, we undertook a review of relevant literature and collaborative discussions focused on the practice of respect in the ICU. We report the output of this process, including a summary of current knowledge, a conceptual framework, and a research program for understanding and improving the practice of respect and dignity in the ICU. We separate our report into findings and proposals. Findings include the following: 1) dignity and respect are interrelated; 2) ICU patients and families are vulnerable to disrespect; 3) violations of respect and dignity appear to be common in the ICU and overlap substantially with dehumanization; 4) disrespect may be associated with both primary and secondary harms; and 5) systemic barriers complicate understanding and the reliable practice of respect in the ICU. Proposals include: 1) initiating and/or expanding a field of research on the practice of respect in the ICU; 2) treating "failures of respect" as analogous to patient safety events and using existing quality and safety mechanisms for improvement; and 3) identifying both benefits and potential unintended consequences of efforts to improve the practice of respect. Respect and dignity are important considerations in the ICU, even as substantial additional research remains to be done.

Ensuring Fairness in Machine Learning to Advance Health Equity.

Machine learning is used increasingly in clinical care to improve diagnosis, treatment selection, and health system efficiency. Because machine-learning models learn from historically collected data, populations that have experienced human and structural biases in the past-called protected groups-are vulnerable to harm by incorrect predictions or withholding of resources. This article describes how model design, biases in data, and the interactions of model predictions with clinicians and patients may exacerbate health care disparities. Rather than simply guarding against these harms passively, machine-learning systems should be used proactively to advance health equity. For that goal to be achieved, principles of distributive justice must be incorporated into model design, deployment, and evaluation. The article describes several technical implementations of distributive justice-specifically those that ensure equality in patient outcomes, performance, and resource allocation-and guides clinicians as to when they should prioritize each principle. Machine learning is providing increasingly sophisticated decision support and population-level monitoring, and it should encode principles of justice to ensure that models benefit all patients.

JAK/STAT inhibitors and other small molecule cytokine antagonists for the treatment of allergic disease.

OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their use in the treatment of atopic dermatitis (AD), asthma, and allergic rhinitis (AR). RESULTS: Allergic diseases represent a spectrum of diseases, including AD, asthma, and AR. For decades, these diseases have been primarily characterized by increased TH2 signaling and downstream inflammation. In recent years, additional research has identified disease phenotypes and subsets of patients with non-Th2 mediated inflammation. The increasing heterogeneity of disease has prompted investigators to move away from wide-ranging treatment approaches with immunosuppressive agents, such as corticosteroids, to consider more targeted immunomodulatory approaches focused on specific pathways. In the past decade, inhibitors that target JAK signaling, PDE4, and CRTH2 have been explored for their potential activity in models of allergic disease and therapeutic benefit in clinical trials. Interestingly, although JAK inhibitors provide an opportunity to interfere with cytokine signaling and could be beneficial in a broad range of allergic diseases, current clinical trials are focused on the treatment of AD. Conversely, both PDE4 and CRTH2 inhibitors have been evaluated in a spectrum of allergic diseases. This review summarizes the varying degrees of success that these small molecules have demonstrated across allergic diseases. CONCLUSION: Emerging therapies currently in development may provide more consistent benefit to patients with allergic diseases by specifically targeting inflammatory pathways important for disease pathogenesis.

Quick Sepsis-related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores for Detecting Clinical Deterioration in Infected Patients outside the Intensive Care Unit.

RATIONALE: The 2016 definitions of sepsis included the quick Sepsis-related Organ Failure Assessment (qSOFA) score to identify high-risk patients outside the intensive care unit (ICU). OBJECTIVES: We sought to compare qSOFA with other commonly used early warning scores. METHODS: All admitted patients who first met the criteria for suspicion of infection in the emergency department (ED) or hospital wards from November 2008 until January 2016 were included. The qSOFA, Systemic Inflammatory Response Syndrome (SIRS), Modified Early Warning Score (MEWS), and the National Early Warning Score (NEWS) were compared for predicting death and ICU transfer. MEASUREMENTS AND MAIN RESULTS: Of the 30,677 included patients, 1,649 (5.4%) died and 7,385 (24%) experienced the composite outcome (death or ICU transfer). Sixty percent (n = 18,523) first met the suspicion criteria in the ED. Discrimination for in-hospital mortality was highest for NEWS (area under the curve [AUC], 0.77; 95% confidence interval [CI], 0.76-0.79), followed by MEWS (AUC, 0.73; 95% CI, 0.71-0.74), qSOFA (AUC, 0.69; 95% CI, 0.67-0.70), and SIRS (AUC, 0.65; 95% CI, 0.63-0.66) (P < 0.01 for all pairwise comparisons). Using the highest non-ICU score of patients, ≥2 SIRS had a sensitivity of 91% and specificity of 13% for the composite outcome compared with 54% and 67% for qSOFA ≥2, 59% and 70% for MEWS ≥5, and 67% and 66% for NEWS ≥8, respectively. Most patients met ≥2 SIRS criteria 17 hours before the combined outcome compared with 5 hours for ≥2 and 17 hours for ≥1 qSOFA criteria. CONCLUSIONS: Commonly used early warning scores are more accurate than the qSOFA score for predicting death and ICU transfer in non-ICU patients. These results suggest that the qSOFA score should not replace general early warning scores when risk-stratifying patients with suspected infection.

Quantifying the Mortality Impact of Do-Not-Resuscitate Orders in the ICU.

OBJECTIVES: We quantified the 28-day mortality effect of preexisting do-not-resuscitate orders in ICUs. DESIGN: Longitudinal, retrospective study of patients admitted to five ICUs at a tertiary university medical center (Beth Israel Deaconess Medical Center, BIDMC, Boston, MA) between 2001 and 2008. INTERVENTION: None. PATIENTS: Two cohorts were defined: patients with do not resuscitate advance directives on day 1 of ICU admission and a control group comprising patients with no limitations of level of care on ICU day 1 (full code). MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality at 28 days after ICU admission. Of 19,007 ICU patients, 1,239 patients (6.5%) had a do-not-resuscitate order on the first day of ICU admission and survived 48 hours in the ICU. We matched those do-not-resuscitate patients with 2,402 patients with full-code status. Twenty-eight day and 1-year mortality were both significantly higher in the do-not-resuscitate group (33.9% vs 18.4% and 60.7% vs 40.2%; p < 0.001, respectively). CONCLUSION: Do-not-resuscitate status is an independent risk factor for ICU mortality. This may reflect severity of illness not captured by other clinical factors, but the perceptions of the treating team related to do-not-resuscitate status could also be causally responsible for increased mortality in patients with do-not-resuscitate status.

An Emergency Department Validation of the SEP-3 Sepsis and Septic Shock Definitions and Comparison With 1992 Consensus Definitions.

STUDY OBJECTIVE: The Third International Consensus Definitions Task Force (SEP-3) proposed revised criteria defining sepsis and septic shock. We seek to evaluate the performance of the SEP-3 definitions for prediction of inhospital mortality in an emergency department (ED) population and compare the performance of the SEP-3 definitions to that of the previous definitions. METHODS: This was a secondary analysis of 3 prospectively collected, observational cohorts of infected ED subjects aged 18 years or older. The primary outcome was all-cause inhospital mortality. In accordance with the SEP-3 definitions, we calculated test characteristics of sepsis (quick Sequential Organ Failure Assessment [qSOFA] score ≥2) and septic shock (vasopressor dependence plus lactate level >2.0 mmol/L) for mortality and compared them to the original 1992 consensus definitions. RESULTS: We identified 7,754 ED patients with suspected infection overall; 117 had no documented mental status evaluation, leaving 7,637 patients included in the analysis. The mortality rate for the overall population was 4.4% (95% confidence interval [CI] 3.9% to 4.9%). The mortality rate for patients with qSOFA score greater than or equal to 2 was 14.2% (95% CI 12.2% to 16.2%), with a sensitivity of 52% (95% CI 46% to 57%) and specificity of 86% (95% CI 85% to 87%) to predict mortality. The original systemic inflammatory response syndrome-based 1992 consensus sepsis definition had a 6.8% (95% CI 6.0% to 7.7%) mortality rate, sensitivity of 83% (95% CI 79% to 87%), and specificity of 50% (95% CI 49% to 51%). The SEP-3 septic shock mortality was 23% (95% CI 16% to 30%), with a sensitivity of 12% (95% CI 11% to 13%) and specificity of 98.4% (95% CI 98.1% to 98.7%). The original 1992 septic shock definition had a 22% (95% CI 17% to 27%) mortality rate, sensitivity of 23% (95% CI 18% to 28%), and specificity of 96.6% (95% CI 96.2% to 97.0%). CONCLUSION: Both the new SEP-3 and original sepsis definitions stratify ED patients at risk for mortality, albeit with differing performances. In terms of mortality prediction, the SEP-3 definitions had improved specificity, but at the cost of sensitivity. Use of either approach requires a clearly intended target: more sensitivity versus specificity.

Targeting the T Helper 2 Inflammatory Axis in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to 25% of children and 10% of adults. The skin of patients with moderate to severe AD is characterized by significant barrier disruption and T helper 2 (Th2)-driven inflammation, which are thought to play a significant role in the pathogenesis of AD. Current management of AD is aimed at suppressing the inflammatory response and restoring the barrier function of the skin, reducing exacerbations, and preventing secondary skin infections. Combinations of treatment strategies are used to alleviate the symptoms of the disease; however, resolution is often temporary, and long-term usage of some of the medications for AD can be associated with significant side effects. Antibody therapies previously approved for other inflammatory diseases have been evaluated in patients with AD. Unfortunately, they have often failed to result in significant clinical improvement. Monoclonal antibodies and novel small molecules currently in development may provide more consistent benefit to patients with AD by specifically targeting the immune and molecular pathways important for the pathogenesis of AD. Here we review the state-of-the-art therapeutics targeting the Th2 axis in AD.

Determining the Ideal Strategy for Ventilator-associated Pneumonia Prevention. Cost-Benefit Analysis.

RATIONALE: Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection with high associated cost and poor patient outcomes. Many strategies for VAP reduction have been evaluated. However, the combination of strategies with the optimal cost-benefit ratio remains unknown. OBJECTIVES: To determine the preferred VAP prevention strategy, both from the hospital and societal perspectives. METHODS: A cost-benefit decision model with a Markov model was constructed. Baseline probability of VAP, death, reintubation, and discharge from the intensive care unit (ICU) alive were ascertained from clinical trial data. Model inputs were obtained from the medical literature and the U.S. Department of Labor; a device cost was obtained from the manufacturer. Sensitivity analyses were completed to test the robustness of model results. MEASUREMENTS AND MAIN RESULTS: Overall least expensive strategy and the strategy with the best cost-benefit ratio, up to a willingness to pay threshold of $50,000-100,000 per case of VAP averted was sought. We examined a total of 120 unique combinations of VAP prevention strategies. The preferred strategy from the hospital perspective included subglottic suction endotracheal tubes, probiotics, and the Institute for Healthcare Improvement VAP Prevention Bundle. The preferred strategy from the point of view of society also included additional prevention measures (oral care with chlorhexidine and selective oral decontamination). No preferred strategies included silver endotracheal tubes or selective gut decontamination. CONCLUSIONS: Despite their infrequent use, current data suggest that the use of prophylactic probiotics and subglottic endotracheal tubes are cost-effective for preventing VAP from the societal and hospital perspectives.