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Abstract BackgroundAcute respiratory failure associated with sepsis contributes to higher in-hospital mortality. Intubation and invasive mechanical ventilation is a common rescue procedure. However, the 2016 International Guidelines for Management of Sepsis and Septic Shock does not provide any recommendation on indication nor timing of intubation. Timely intubation may improve outcome. The decision to intubate those patients is often hampered by the fear of further hemodynamic deterioration following intubation. MethodsThis study aimed at evaluating the impact of timely intubation on outcome in sepsis associated respiratory failure. We conducted an ancillary analysis of a prospective registry od adult ICU patients with septic shock admitted to the medical ICU in a tertiary medical center, between April 30th, 2014 and December 31st, 2017. All cases of sepsis with lactate >4 mmol/L, mean arterial pressure <65 mmHg, or vasopressor use after 30 mL/kg fluid boluses and suspected or confirmed infection. Patients who remained hospitalized at 24 hours following sepsis onset were separated into intubated and non-intubated groups. The primary outcome was hospital mortality. Univariate and multivariable analyses were used, adjusted for admission characteristics and stabilization of shock within 6 hours. In a secondary analysis, time-dependent propensity score matching was used to match intubated and non-intubated patients.ResultsWe identified 345 (33%) patients intubated within 24 hours and 707 (67%) not intubated. Intubated patients were younger, transferred more often from an outside facility, had higher severity of illness scores, more lung infection, achieved blood pressure goals more often but less often lactate normalization within 6 hours. The crude in-hospital mortality was higher, 89 (26%) vs. 82 (12%), p<0.001, as were ICU mortality, and ICU and hospital length of stay. After adjustment, intubation showed no effect on hospital mortality but fewer hospital-free days through day 28. After 1:1 propensity score matching, there was no difference in hospital mortality, but fewer hospital-free days in the intubated group. ConclusionsIntubation within 24 hours of sepsis onset was safe and not associated with hospital mortality, but was associated with less 28-day hospital-free days. Intubation should not be discouraged in appropriate patients with septic shock.

This work investigates the use of an intelligent and unobstructive sensing technique for maintaining vehicle cabin’s indoor air quality while simultaneously assessing the driver metabolic rate. CO2 accumulation patterns are of great interest because CO2 can have negative cognitive effects at higher concentrations and also since CO2 accumulation rate can potentially be used to determine a person’s metabolic rate. The management of the vehicle’s ventilation system was controlled by periodically alternating the air recirculation mode within the cabin, which was actuated based on the CO2 levels inside the vehicle’s cabin. The CO2 accumulation periods were used to assess the driver’s metabolic rate, using a model that considered the vehicle’s air exchange rate. In the process of the method optimization, it was found that the vehicle’s air exchange rate (λ [h−1]) depends on the vehicle speeds, following the relationship: λ = 0.060 × (speed) − 0.88 when driving faster than 17 MPH. An accuracy level of 95% was found between the new method to assess the driver’s metabolic rate (1620 ± 140 kcal/day) and the reference method of indirect calorimetry (1550 ± 150 kcal/day) for a total of N = 16 metabolic assessments at various vehicle speeds. The new sensing method represents a novel approach for unobstructive assessment of driver metabolic rate while maintaining indoor air quality within the vehicle cabin.

BackgroundMany young women with newly diagnosed breast cancer are interested in future pregnancies. Prospective data regarding fertility interest and reproductive patterns after diagnosis are needed to counsel patients.MethodsThe Young Women's Breast Cancer Study is a multicenter, prospective cohort of women who were diagnosed with breast cancer at age ≤40 years between 2006 and 2016. Women complete surveys at baseline, every 6 months for 3 years, then annually. Here, the authors describe fertility interest and pregnancies within 5 years of diagnosis for women with stage 0 through III breast cancer.ResultsOf 1026 eligible participants, 368 (36%) reported interest in future biologic children at least once within 5 years after diagnosis, including 16% at 5 years after diagnosis. Among 130 women who attempted to become pregnant, 90 (69.2%) conceived; and, among 896 women who did not attempt to conceive, 18 (2.0%) became pregnant, with a total of 152 pregnancies resulting in 91 live births. Factors associated with pregnancy included younger versus older age at diagnosis (aged ≤30 vs 36‐40 years: odds ratio [OR], 6.63; 95% CI, 3.18‐13.83; P < .0001; aged 31‐35 vs 36‐40 years: OR, 5.86; 95% CI, 3.37‐10.17; P < .0001) and being nulliparous versus parous (OR, 2.66; 95% CI, 1.56‐4.53; P = .001). The receipt of endocrine therapy versus no endocrine therapy (OR, 0.35; 95% CI, 0.20‐0.59; P = .001) was inversely associated with pregnancy.ConclusionsMany women remain interested in future fertility in the 4 years after a breast cancer diagnosis, indicating that longitudinal fertility discussions are needed. Although a minority of those interested in having children attempted to become pregnant in the first 5 years, most who attempted to conceive did so and had live births.

We previously applied Systematic Evolution of Ligands by EXponential enrichment (SELEX) technology to identify myelin-specific DNA aptamers, using crude mouse central nervous system myelin as bait. This selection identified a 40-nucleotide aptamer (LJM-3064). Multiple biotinylated LJM-3064 molecules were conjugated to a streptavidin core to mimic a multimeric immunoglobulin M (IgM) antibody, generating 3064-BS-streptavidin (Myaptavin-3064). We previously showed that Myaptavin-3064 induces remyelination in the Theiler’s murine encephalomyelitis virus (TMEV) model of chronic spinal cord demyelination. While details of target binding and the mechanism of action remain unclear, we hypothesized that Myaptavin-3064 induces remyelination by binding to oligodendrocytes (OLs). We now report the results of binding assays using the human oligodendroglioma (HOG) cell line, applying both flow cytometry and immunocytochemistry (IC) to assay aptamer conjugate binding to cells. IC assays were applied to compare aptamer conjugate binding to primary embryonic mouse mixed cortical cultures and primary adult rat mixed glial cultures. We show that Myaptavin-3064 binds to HOG cells, with increased binding upon differentiation. In contrast, a negative control aptamer conjugate, 3060-BS, which did not promote central nervous system (CNS) remyelination, does not bind to HOG cells. Myaptavin-3064 did not bind to lung (L2) or kidney (BHK) cell lines. Total internal reflection fluorescence (TIRF) imaging indicates that Myaptavin-3064 binds at the cell membrane of live cells. In addition to HOG cells, Myaptavin-3064 binds to adult rat OLs, but not to embryonic mouse mixed cortical cultures. These data support the hypothesis that Myaptavin-3064 binds to a surface molecule on both rodent and human OLs in a manner that triggers a remyelination signal pathway.

Objectives: To develop and verify a digital twin model of critically ill patient using the causal artificial intelligence approach to predict the response to specific treatment during the first 24 hours of sepsis. Design: Directed acyclic graphs were used to define explicitly the causal relationship among organ systems and specific treatments used. A hybrid approach of agent-based modeling, discrete-event simulation, and Bayesian network was used to simulate treatment effect across multiple stages and interactions of major organ systems (cardiovascular, neurologic, renal, respiratory, gastrointestinal, inflammatory, and hematology). Organ systems were visualized using relevant clinical markers. The application was iteratively revised and debugged by clinical experts and engineers. Agreement statistics was used to test the performance of the model by comparing the observed patient response versus the expected response (primary and secondary) predicted by digital twin. Setting: Medical ICU of a large quaternary- care academic medical center in the United States. Patients or Subjects: Adult (> 18 year yr old), medical ICU patients were included in the study. Interventions: No additional interventions were made beyond the standard of care for this study. Measurements and Main Results: During the verification phase, model performance was prospectively tested on 145 observations in a convenience sample of 29 patients. Median age was 60 years (54–66 d) with a median Sequential Organ Failure Assessment score of 9.5 (interquartile range, 5.0–14.0). The most common source of sepsis was pneumonia, followed by hepatobiliary. The observations were made during the first 24 hours of the ICU admission with one-step interventions, comparing the output in the digital twin with the real patient response. The agreement between the observed versus and the expected response ranged from fair (kappa coefficient of 0.41) for primary response to good (kappa coefficient of 0.65) for secondary response to the intervention. The most common error detected was coding error in 50 observations (35%), followed by expert rule error in 29 observations (20%) and timing error in seven observations (5%). Conclusions: We confirmed the feasibility of development and prospective testing of causal artificial intelligence model to predict the response to treatment in early stages of critical illness. The availability of qualitative and quantitative data and a relatively short turnaround time makes the ICU an ideal environment for development and testing of digital twin patient models. An accurate digital twin model will allow the effect of an intervention to be tested in a virtual environment prior to use on real patients.

Age-associated T RM cell malfunction supports chronic lung inflammation and tissue fibrosis after respiratory viral infection.