CodonBERT large language model for mRNA vaccines.

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties, including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs, which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods, including on a new flu vaccine data set.

B cells and tertiary lymphoid structures promote immunotherapy response.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Long ties, disruptive life events, and economic prosperity.

Social networks shape and reflect economic life. Prior studies have identified long ties, which connect people who lack mutual contacts, as a correlate of individuals' success within firms and places' economic prosperity. However, we lack population-scale evidence of the individual-level link between long ties and economic prosperity, and why some people have more long ties remains obscure. Here, using a social network constructed from interactions on Facebook, we establish a robust association between long ties and economic outcomes and study disruptive life events hypothesized to cause formation of long ties. Consistent with prior aggregated results, administrative units with a higher fraction of long ties tend to have higher-income and economic mobility. Individuals with more long ties live in higher-income places and have higher values of proxies for economic prosperity (e.g., using more Internet-connected devices and making more donations). Furthermore, having stronger long ties (i.e., with higher intensity of interaction) is associated with better outcomes, consistent with an advantage from the structural diversity constituted by long ties, rather than them being weak ties per se. We then study the role of disruptive life events in the formation of long ties. Individuals who have migrated between US states, have transferred between high schools, or have attended college out-of-state have a higher fraction of long ties among their contacts many years after the event. Overall, these results suggest that long ties are robustly associated with economic prosperity and highlight roles for important life experiences in developing and maintaining long ties.

Removal of Small, Asymptomatic Kidney Stones and Incidence of Relapse.

BACKGROUND: The benefits of removing small (≤6 mm), asymptomatic kidney stones endoscopically is unknown. Current guidelines leave such decisions to the urologist and the patient. A prospective study involving older, nonendoscopic technology and some retrospective studies favor observation. However, published data indicate that about half of small renal stones left in place at the time that larger stones were removed caused other symptomatic events within 5 years after surgery. METHODS: We conducted a multicenter, randomized, controlled trial in which, during the endoscopic removal of ureteral or contralateral kidney stones, remaining small, asymptomatic stones were removed in 38 patients (treatment group) and were not removed in 35 patients (control group). The primary outcome was relapse as measured by future emergency department visits, surgeries, or growth of secondary stones. RESULTS: After a mean follow-up of 4.2 years, the treatment group had a longer time to relapse than the control group (P<0.001 by log-rank test). The restricted mean (±SE) time to relapse was 75% longer in the treatment group than in the control group (1631.6±72.8 days vs. 934.2±121.8 days). The risk of relapse was 82% lower in the treatment group than the control group (hazard ratio, 0.18; 95% confidence interval, 0.07 to 0.44), with 16% of patients in the treatment group having a relapse as compared with 63% of those in the control group. Treatment added a median of 25.6 minutes (interquartile range, 18.5 to 35.2) to the surgery time. Five patients in the treatment group and four in the control group had emergency department visits within 2 weeks after surgery. Eight patients in the treatment group and 10 in the control group reported passing kidney stones. CONCLUSIONS: The removal of small, asymptomatic kidney stones during surgery to remove ureteral or contralateral kidney stones resulted in a lower incidence of relapse than nonremoval and in a similar number of emergency department visits related to the surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Veterans Affairs Puget Sound Health Care System; ClinicalTrials.gov number, NCT02210650.).

Early Active Mobilization during Mechanical Ventilation in the ICU.

BACKGROUND: Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability. METHODS: We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization. RESULTS: The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P = 0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P = 0.005). CONCLUSIONS: Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).

Representations of lipid nanoparticles using large language models for transfection efficiency prediction.

MOTIVATION: Lipid nanoparticles (LNPs) are the most widely used vehicles for mRNA vaccine delivery. The structure of the lipids composing the LNPs can have a major impact on the effectiveness of the mRNA payload. Several properties should be optimized to improve delivery and expression including biodegradability, synthetic accessibility, and transfection efficiency. RESULTS: To optimize LNPs, we developed and tested models that enable the virtual screening of LNPs with high transfection efficiency. Our best method uses the lipid Simplified Molecular-Input Line-Entry System (SMILES) as inputs to a large language model. Large language model-generated embeddings are then used by a downstream gradient-boosting classifier. As we show, our method can more accurately predict lipid properties, which could lead to higher efficiency and reduced experimental time and costs. AVAILABILITY AND IMPLEMENTATION: Code and data links available at: https://github.com/Sanofi-Public/LipoBART.

Impact of High Dose Early Mobilization on Outcomes for Patients with Diabetes: A Secondary Analysis of the TEAM Trial.

RATIONALE: Patients with diabetes represent almost 20% of all ICU admissions and might respond differently to high dose early active mobilization. OBJECTIVES: To assess whether diabetes modified the relationship between the dose of early mobilization on clinical outcomes in the TEAM trial. METHODS: All TEAM trial patients were included. The primary outcome was days alive and out of hospital at day 180. Secondary outcomes included 180-day mortality and long-term functional outcomes at day 180. Logistic and median regression models were used to explore the effect of high dose early mobilization on outcomes by diabetes status. MEASUREMENTS AND MAIN RESULTS: All 741 patients from the original trial were included. Of these, 159 patients (21.4%) had diabetes. Patients with diabetes had a lower number of days alive and out of hospital at day 180 (124 [0-153] vs. 147 [82-164], p = 0.013), and higher 180-day mortality (30% vs. 18%, p = 0.044). In patients receiving high dose early mobilization, days alive and out of hospital at day 180 was 73.0 (0.0 - 144.5) in patients with diabetes and 146.5 (95.8 - 163.0) in patients without diabetes (p for interaction = 0.108). However, in patients with diabetes, high dose early mobilization increased the odds of mortality at 180 days (adjusted odds ratio 3.47; 95% confidence interval [CI], 1.67-7.61, p value for interaction, 0.001). CONCLUSIONS: In this secondary analysis of the TEAM trial, in patients with diabetes, a high dose early mobilization strategy did not significantly decrease the number of days alive and out of hospital at day 180 but it increased 180-day mortality.

Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study.

BACKGROUND: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment. METHODS: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry. FINDINGS: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes. INTERPRETATION: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.

Sex Differences in Vital Organ Support Provided to ICU Patients.

OBJECTIVES: Critically ill women may receive less vital organ support than men but the mortality impact of this differential treatment remains unclear. We aimed to quantify sex differences in vital organ support provided to adult ICU patients and describe the relationship between sex, vital organ support, and mortality. DESIGN: In this retrospective observational study, we examined the provision of invasive ventilation (primary outcome), noninvasive ventilation, vasoactive medication, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), or any one of these five vital organ supports in women compared with men. We performed logistic regression investigating the association of sex with each vital organ support, adjusted for illness severity, diagnosis, preexisting treatment limitation, year, and hospital. We performed logistic regression for hospital mortality adjusted for the same variables, stratified by vital organ support (secondary outcome). SETTING AND PATIENTS: ICU admissions in the Australia and New Zealand Intensive Care Society Adult Patient Database 2018-2021. This registry records admissions from 90% of ICUs in the two nations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined 699,535 ICU admissions (43.7% women) to 199 ICUs. After adjustment, women were less likely than men to receive invasive ventilation (odds ratio [OR], 0.64; 99% CI, 0.63-0.65) and each other organ support except ECMO. Women had lower adjusted hospital mortality overall (OR, 0.94; 99% CI, 0.91-0.97). Among patients who did not receive any organ support, women had significantly lower adjusted hospital mortality (OR, 0.82; 99% CI, 0.76-0.88); among patients who received any organ support women and men were equally likely to die (OR, 1.01; 99% CI, 0.97-1.04). CONCLUSIONS: Women received significantly less vital organ support than men in ICUs in Australia and New Zealand. However, our findings suggest that women may not be harmed by this conservative approach to treatment.

Randomized Controlled Trial of Ultrasonic Propulsion-Facilitated Clearance of Residual Kidney Stone Fragments vs Observation.

PURPOSE: Ultrasonic propulsion is an investigational procedure for awake patients. Our purpose was to evaluate whether ultrasonic propulsion to facilitate residual kidney stone fragment clearance reduced relapse. MATERIALS AND METHODS: This multicenter, prospective, open-label, randomized, controlled trial used single block randomization (1:1) without masking. Adults with residual fragments (individually ≤5 mm) were enrolled. Primary outcome was relapse as measured by stone growth, a stone-related urgent medical visit, or surgery by 5 years or study end. Secondary outcomes were fragment passage within 3 weeks and adverse events within 90 days. Cumulative incidence of relapse was estimated using the Kaplan-Meier method. Log-rank test was used to compare the treatment (ultrasonic propulsion) and control (observation) groups. RESULTS: The trial was conducted from May 9, 2015, through April 6, 2024. Median follow-up (interquartile range) was 3.0 (1.8-3.2) years. The treatment group (n = 40) had longer time to relapse than the control group (n = 42; P < .003). The restricted mean time-to-relapse was 52% longer in the treatment group than in the control group (1530 ± 92 days vs 1009 ± 118 days), and the risk of relapse was lower (hazard ratio 0.30, 95% CI 0.13-0.68) with 8 of 40 and 21 of 42 participants, respectively, experiencing relapse. Omitting 3 participants not asked about passage, 24 treatment (63%) and 2 control (5%) participants passed fragments within 3 weeks of treatment. adverse events were mild, transient, and self-resolving, and were reported in 25 treated participants (63%) and 17 controls (40%). CONCLUSIONS: Ultrasonic propulsion reduced relapse and added minimal risk. CLINICAL TRIAL REGISTRATION NO.: NCT02028559.

Fetal CCL2 signaling mediates offspring social behavior and recapitulates effects of prenatal stress.

Maternal stress during pregnancy is prevalent and associated with increased risk of neurodevelopmental disorders in the offspring. Maternal and offspring immune dysfunction has been implicated as a potential mechanism by which prenatal stress shapes offspring neurodevelopment; however, the impact of prenatal stress on the developing immune system has yet to be elucidated. Furthermore, there is evidence that the chemokine C-C motif chemokine ligand 2 (CCL2) plays a key role in mediating the behavioral sequelae of prenatal stress. Here, we use an established model of prenatal restraint stress in mice to investigate alterations in the fetal immune system, with a focus on CCL2. In the placenta, stress led to a reduction in CCL2 and Ccr2 expression with a concomitant decrease in leukocyte number. However, the fetal liver exhibited an inflammatory phenotype, with upregulation of Ccl2, Il6, and Lbp expression, along with an increase in pro-inflammatory Ly6CHi monocytes. Prenatal stress also disrupted chemokine signaling and increased the number of monocytes and microglia in the fetal brain. Furthermore, stress increased Il1b expression by fetal brain CD11b+ microglia and monocytes. Finally, intra-amniotic injections of recombinant mouse CCL2 partially recapitulated the social behavioral deficits in the adult offspring previously observed in the prenatal restraint stress model. Altogether, these data suggest that prenatal stress led to fetal inflammation, and that fetal CCL2 plays a role in shaping offspring social behavior.

Modulation of anxiety-like behavior in galactooligosaccharide-fed mice: A potential role for bacterial tryptophan metabolites and reduced microglial reactivity.

Prebiotic galactooligosaccharides (GOS) reduce anxiety-like behaviors in mice and humans. However, the biological pathways behind these behavioral changes are not well understood. To begin to study these pathways, we utilized C57BL/6 mice that were fed a standard diet with or without GOS supplementation for 3 weeks prior to testing on the open field. After behavioral testing, colonic contents and serum were collected for bacteriome (16S rRNA gene sequencing, colonic contents only) and metabolome (UPLC-MS, colonic contents and serum data) analyses. As expected, GOS significantly reduced anxiety-like behavior (i.e., increased time in the center) and decreased cytokine gene expression (Tnfa and Ccl2) in the prefrontal cortex. Notably, time in the center of the open field was significantly correlated with serum methyl-indole-3-acetic acid (methyl-IAA). This metabolite is a methylated form of indole-3-acetic acid (IAA) that is derived from bacterial metabolism of tryptophan. Sequencing analyses showed that GOS significantly increased Lachnospiraceae UCG006 and Akkermansia; these taxa are known to metabolize both GOS and tryptophan. To determine the extent to which methyl-IAA can affect anxiety-like behavior, mice were intraperitoneally injected with methyl-IAA. Mice given methyl-IAA had a reduction in anxiety-like behavior in the open field, along with lower Tnfa in the prefrontal cortex. Methyl-IAA was also found to reduce TNF-α (as well as CCL2) production by LPS-stimulated BV2 microglia. Together, these data support a novel pathway through which GOS reduces anxiety-like behaviors in mice and suggests that the bacterial metabolite methyl-IAA reduces microglial cytokine and chemokine production, which in turn reduces anxiety-like behavior.

EzBioCloud: a genome-driven database and platform for microbiome identification and discovery.

With the continued evolution of DNA sequencing technologies, the role of genome sequence data has become more integral in the classification and identification of Bacteria and Archaea. Six years after introducing EzBioCloud, an integrated platform representing the taxonomic hierarchy of Bacteria and Archaea through quality-controlled 16S rRNA gene and genome sequences, we present an updated version, that further refines and expands its capabilities. The current update recognizes the growing need for accurate taxonomic information as defining a species increasingly relies on genome sequence comparisons. We also incorporated an advanced strategy for addressing underrepresented or less studied lineages, bolstering the comprehensiveness and accuracy of our database. Our rigorous quality control protocols remain, where whole-genome assemblies from the NCBI Assembly Database undergo stringent screening to remove low-quality sequence data. These are then passed through our enhanced identification bioinformatics pipeline which initiates a 16S rRNA gene similarity search and then calculates the average nucleotide identity (ANI). For genome sequences lacking a 16S rRNA sequence and without a closely related genomic representative for ANI calculation, we apply a different ANI approach using bacterial core genes for improved taxonomic placement (core gene ANI, cgANI). Because of the increase in genome sequences available in NCBI and our newly introduced cgANI method, EzBioCloud now encompasses a total of 109 835 species, of which 21 964 have validly published names. 47 896 are candidate species identified either through 16S rRNA sequence similarity (phylotypes) or through whole genome ANI (genomospecies), and the remaining 39 975 were positioned in the taxonomic tree by cgANI (species clusters). Our EzBioCloud database is accessible at www.ezbiocloud.net/db.

Sepsis mortality among patients with haematological malignancy admitted to intensive care 2000-2022: a binational cohort study.

BACKGROUND: Sepsis occurs in 12-27% of patients with haematological malignancy within a year of diagnosis. Sepsis mortality has improved in non-cancer patients in the last two decades, but longitudinal trends in patients with haematological malignancy are not well characterised. We aimed to compare outcomes, including temporal changes, in patients with and without a haematological malignancy admitted to ICU with a primary diagnosis of sepsis in Australia and New Zealand over the past two decades. METHODS: We performed a retrospective cohort study of 282,627 patients with a primary intensive care unit (ICU) admission diagnosis of sepsis including 17,313 patients with haematological malignancy, admitted to 216 intensive care units (ICUs) in Australia or New Zealand between January 2000 and December 2022. Annual crude and adjusted in-hospital mortality were reported. Risk factors for in-hospital mortality were determined using a mixed methods logistic regression model and were used to calculate annual changes in mortality. RESULTS: In-hospital sepsis mortality decreased in patients with haematological malignancy, from 55.6% (95% CI 46.5-64.6%) in 2000 to 23.1% (95% CI 20.8-25.5%) in 2021. In patients without haematological malignancy mortality decreased from 33.1% (95% CI 31.3-35.1%) to 14.4% (95% CI 13.8-14.8%). This decrease remained significant after adjusting for mortality predictors including age, SOFA score and comorbidities, as estimated by adjusted annual odds of in-hospital death. The reduction in odds of death was of greater magnitude in patients with haematological malignancy than those without (OR 0.954, 95% CI 0.947-0.961 vs. OR 0.968, 95% CI 0.966-0.971, p < 0.001). However, absolute risk of in-hospital mortality remained higher in patients with haematological malignancy. Older age, higher SOFA score, presence of comorbidities, and mechanical ventilation were associated with increased mortality. Leukopenia (white cell count < 1.0 × 109 cells/L) was not associated with increased mortality in patients with haematological malignancy (p = 0.60). CONCLUSIONS: Sepsis mortality has improved in patients with haematological malignancy admitted to ICU. However, mortality remains higher in patients with haematological malignancy than those without.

FRailty in Australian patients admitted to Intensive care unit after eLective CANCER-related SURGery: a retrospective multicentre cohort study (FRAIL-CANCER-SURG study).

BACKGROUND: The association between frailty and short-term and long-term outcomes in patients receiving elective surgery for cancer remains unclear, particularly in those admitted to the ICU. METHODS: In this multicentre retrospective cohort study, we included adults ≥16 yr old admitted to 158 ICUs in Australia from January 1, 2018 to March 31, 2022 after elective surgery for cancer. We investigated the association between frailty and survival time up to 4 yr (primary outcome), adjusting for a prespecified set of covariates. We analysed how this association changed in specific subgroups (age categories [<65, 65-80, ≥80 yr], and those who survived hospitalisation), and over time by splitting the survival information at monthly intervals. RESULTS: We included 35,848 patients (median follow-up: 18.1 months [inter-quartile range: 8.3-31.1 months], 19,979 [56.1%] male, median age 69.0 yr [inter-quartile range: 58.8-76.0 yr]). Some 3502 (9.8%) patients were frail (defined as clinical frailty scale ≥5). Frailty was associated with lower survival (hazard ratio: 1.72, 95% confidence interval [CI]: 1.59-1.86 compared with clinical frailty scale ≤4); this was concordant across several sensitivity analyses. Frailty was most strongly associated with mortality early on in follow-up, up to 10 months (hazard ratio: 1.39, 95% CI: 1.03-1.86), but this association plateaued, and its predictive capacity subsequently diminished with time up until 4 yr (1.96, 95% CI: 0.73-5.28). Frailty was associated with similar effects when stratified based on age, and in those who survived hospitalisation. CONCLUSIONS: Frailty was associated with poorer outcomes after an ICU admission after elective surgery for cancer, particularly in the short term. However, its predictive capacity with time diminished, suggesting a potential need for longitudinal reassessment to ensure appropriate prognostication in this population.

Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III).

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 µg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

Effect of a person-centred goals-of-care form and clinical communication training on shared decision-making and outcomes in an acute hospital: a prospective longitudinal interventional study.

BACKGROUND: Patients with a life-limiting illness (LLI) requiring hospitalisation have a high likelihood of deterioration and 12-month mortality. To avoid non-aligned care, we need to understand our patients' goals and values. AIM: To describe the association between the implementation of a shared decision-making (SDM) programme and documentation of goals of care (GoC) for hospitalised patients with LLI. METHODS: A prospective longitudinal interventional study of patients admitted to acute general medicine wards in an Australian tertiary hospital over 5 years was conducted. A SDM programme with a new GoC form, communication training and clinical support was implemented. The primary outcome was the proportion of patients with a documented person-centred GoC discussion (PCD). Clinical outcomes included hospital utilisation and 90-day mortality. RESULTS: 1343 patients were included. The proportion of patients with PCDs increased from 0% to 35.4% (adjusted odds ratio (aOR), 2.38; 95% confidence interval (CI), 2.01-2.82; P < 0.001). During this time, median hospital length of stay decreased from 8 days (interquartile range (IQR), 4-14) to 6 days (IQR, 3-11) (adjusted estimate effect, -0.38; 95% CI, -0.64 to -0.11; P = 0.005) and rapid response team activation from 28% to 13% (aOR, 0.87; 95% CI, 0.78-0.97; P value = 0.01). Documented treatment preference of high-dependency unit care decreased from 39.7% to 24.4% (aOR, 0.81; 95% CI, 0.73-0.89; P value < 0.001), and ward-based care increased from 31.9% to 55.1% (aOR, 1.24; 95% CI, 1.14-1.36; P value < 0.001). CONCLUSION: The implementation of a SDM programme was associated with increased documentation of person-centred GoC, changed patient treatment preference to lower intensity care and reduced hospital utilisation.

Development of an Automated Ultrasound Signal Indicator of Lung Interstitial Syndrome.

OBJECTIVES: The number and distribution of lung ultrasound (LUS) imaging artifacts termed B-lines correlate with the presence of acute lung disease such as infection, acute respiratory distress syndrome (ARDS), and pulmonary edema. Detection and interpretation of B-lines require dedicated training and is machine and operator-dependent. The goal of this study was to identify radio frequency (RF) signal features associated with B-lines in a cohort of patients with cardiogenic pulmonary edema. A quantitative signal indicator could then be used in a single-element, non-imaging, wearable, automated lung ultrasound sensor (LUSS) for continuous hands-free monitoring of lung fluid. METHODS: In this prospective study a 10-zone LUS exam was performed in 16 participants, including 12 patients admitted with acute cardiogenic pulmonary edema (mean age 60 ± 12 years) and 4 healthy controls (mean age 44 ± 21). Overall,160 individual LUS video clips were recorded. The LUS exams were performed with a phased array probe driven by an open-platform ultrasound system with simultaneous RF signal collection. RF data were analyzed offline for candidate B-line indicators based on signal amplitude, temporal variability, and frequency spectrum; blinded independent review of LUS images for the presence or absence of B-lines served as ground truth. Predictive performance of the signal indicators was determined with receiving operator characteristic (ROC) analysis with k-fold cross-validation. RESULTS: Two RF signal features-temporal variability of signal amplitude at large depths and at the pleural line-were strongly associated with B-line presence. The sensitivity and specificity of a combinatorial indicator were 93.2 and 58.5%, respectively, with cross-validated area under the ROC curve (AUC) of 0.91 (95% CI = 0.80-0.94). CONCLUSION: A combinatorial signal indicator for use with single-element non-imaging LUSS was developed to facilitate continuous monitoring of lung fluid in patients with respiratory illness.

Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial.

BACKGROUND: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. OBJECTIVE: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. DESIGN: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583). SETTING: Primary/community care in Australia and the United States. PARTICIPANTS: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). INTERVENTION: 100 mg of aspirin daily or placebo. MEASUREMENTS: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. RESULTS: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. LIMITATIONS: Hemoglobin was measured annually. No data were available on causes of anemia. CONCLUSION: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. PRIMARY FUNDING SOURCE: National Institutes of Health and Australian National Health and Medical Research Council.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.