Clinical and biochemical responses to treatment of uncomplicated severe acute malnutrition: a multicenter observational cohort from the OptiDiag study.

BACKGROUND: Severe acute malnutrition (SAM) can be diagnosed using weight-for-height Z-score (WHZ) and/or mid-upper arm circumference (MUAC). Although some favor using MUAC alone, valuing its presumed ability to identify children at greatest need for nutritional care, the functional severity and physiological responses to treatment in children with varying deficits in WHZ and MUAC remain inadequately characterized. OBJECTIVE: We aimed to compare clinical and biochemical responses to treatment in children with 1) both low MUAC and low WHZ, 2) low MUAC-only, and 3) low WHZ-only. METHODS: A multicenter, observational cohort study was conducted in children aged 6-59 mo with nonedematous, uncomplicated SAM in Bangladesh, Burkina Faso, and Liberia. Anthropometric measurements and critical indicators were collected 3 times during treatment; metrics included clinical status, nutritional status, viability, and serum leptin, a biomarker of mortality risk in SAM. RESULTS: Children with combined MUAC and WHZ deficits had greater increases in leptin levels during treatment than those with low MUAC alone, showing a 34.4% greater increase on the second visit (95% confidence interval [CI]: 7.6%, 43.6%; P = 0.02) and a 34.3% greater increase on the third visit (95% CI: 13.2%, 50.3%; P = 0.01). Similarly, weight gain velocity was higher by 1.56 g/kg/d in the combined deficit group (95% CI: 0.38, 2.75; P = 0.03) compared with children with low MUAC-only. Children with combined deficits had higher rates of iron deficiency and wasting while those with low WHZ alone and combined deficits had higher rates of tachypnea and pneumonia during treatment. CONCLUSIONS: Given the comparable treatment responses of children with low WHZ alone and those with low MUAC alone, and the greater vulnerability at admission and during treatment in those with combined deficits, our findings support retaining WHZ as an independent diagnostic and admission criterion of SAM, alongside MUAC. This trial was registered at www. CLINICALTRIALS: gov/study/NCT03400930 as NCT03400930.

Open-source machine learning pipeline automatically flags instances of acute respiratory distress syndrome from electronic health records.

Physicians could greatly benefit from automated diagnosis and prognosis tools to help address information overload and decision fatigue. Intensive care physicians stand to benefit greatly from such tools as they are at particularly high risk for those factors. Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition affecting >10% of critical care patients and has a mortality rate over 40%. However, recognition rates for ARDS have been shown to be low (30-70%) in clinical settings. In this work, we present a reproducible computational pipeline that automatically adjudicates ARDS on retrospective datasets of mechanically ventilated adult patients. This pipeline automates the steps outlined by the Berlin Definition through implementation of natural language processing tools and classification algorithms. We train an XGBoost model on chest imaging reports to detect bilateral infiltrates, and another on a subset of attending physician notes labeled for the most common ARDS risk factor in our data. Both models achieve high performance-a minimum area under the receiver operating characteristic curve (AUROC) of 0.86 for adjudicating chest imaging reports in out-of-bag test sets, and an out-of-bag AUROC of 0.85 for detecting a diagnosis of pneumonia. We validate the entire pipeline on a cohort of MIMIC-III encounters and find a sensitivity of 93.5% - an extraordinary improvement over the 22.6% ARDS recognition rate reported for these encounters - along with a specificity of 73.9%. We conclude that our reproducible, automated diagnostic pipeline exhibits promising accuracy, generalizability, and probability calibration, thus providing a valuable resource for physicians aiming to enhance ARDS diagnosis and treatment strategies. We surmise that proper implementation of the pipeline has the potential to aid clinical practice by facilitating the recognition of ARDS cases at scale.

Defining the Time-limited Trial for Patients with Critical Illness: An Official American Thoracic Society Workshop Report.

In critical care, the specific, structured approach to patient care known as a "time-limited trial" has been promoted in the literature to help patients, surrogate decision makers, and clinicians navigate consequential decisions about life-sustaining therapy in the face of uncertainty. Despite promotion of the time-limited trial approach, a lack of consensus about its definition and essential elements prevents optimal clinical use and rigorous evaluation of its impact. The objectives of this American Thoracic Society Workshop Committee were to establish a consensus definition of a time-limited trial in critical care, identify the essential elements for conducting a time-limited trial, and prioritize directions for future work. We achieved these objectives through a structured search of the literature, a modified Delphi process with 100 interdisciplinary and interprofessional stakeholders, and iterative committee discussions. We conclude that a time-limited trial for patients with critical illness is a collaborative plan among clinicians and a patient and/or their surrogate decision makers to use life-sustaining therapy for a defined duration, after which the patient's response to therapy informs the decision to continue care directed toward recovery, transition to care focused exclusively on comfort, or extend the trial's duration. The plan's 16 essential elements follow four sequential phases: consider, plan, support, and reassess. We acknowledge considerable gaps in evidence about the impact of time-limited trials and highlight a concern that if inadequately implemented, time-limited trials may perpetuate unintended harm. Future work is needed to better implement this defined, specific approach to care in practice through a person-centered equity lens and to evaluate its impact on patients, surrogates, and clinicians.

Ascorbate protects human kidney organoids from damage induced by cell-free hemoglobin.

Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2. To better model the intact kidney, we cultured human kidney organoids derived from induced pluripotent stem cells. We treated human kidney organoids grown using both three-dimensional and transwell protocols with CFH for 48 h. We found evidence for increased tubular toxicity, oxidative stress, mitochondrial fragmentation, endothelial cell injury and injury-associated transcripts compared to those of the untreated control group. To evaluate the protective effect of clinically available small molecules, we co-treated CFH-injured organoids with ascorbate (vitamin C) or acetaminophen for 48 h. We found significantly decreased toxicity, preservation of endothelial cells and reduced mitochondrial fragmentation in the group receiving ascorbate following CFH treatment. This study provides direct evidence that ascorbate or ascorbic acid protects human kidney cells from CFH-induced damage such as that in sepsis-associated acute kidney injury.

Validation of a tool for estimating clinician recognition of ARDS using data from the international LUNG SAFE study.

Under-recognition of acute respiratory distress syndrome (ARDS) by clinicians is an important barrier to adoption of evidence-based practices such as low tidal volume ventilation. The burden created by the COVID-19 pandemic makes it even more critical to develop scalable data-driven tools to improve ARDS recognition. The objective of this study was to validate a tool for accurately estimating clinician ARDS recognition rates using discrete clinical characteristics easily available in electronic health records. We conducted a secondary analysis of 2,705 ARDS and 1,261 non-ARDS hypoxemic patients in the international LUNG SAFE cohort. The primary outcome was validation of a tool that estimates clinician ARDS recognition rates from health record data. Secondary outcomes included the relative impact of clinical characteristics on tidal volume delivery and clinician documentation of ARDS. In both ARDS and non-ARDS patients, greater height was associated with lower standardized tidal volume (mL/kg PBW) (ARDS: adjusted ß = -4.1, 95% CI -4.5 --3.6; non-ARDS: ß = -7.7, 95% CI -8.8 --6.7, P<0.00009 [where α = 0.01/111 with the Bonferroni correction]). Standardized tidal volume has already been normalized for patient height, and furthermore, height was not associated with clinician documentation of ARDS. Worsening hypoxemia was associated with both increased clinician documentation of ARDS (ß = -0.074, 95% CI -0.093 --0.056, P<0.00009) and lower standardized tidal volume (ß = 1.3, 95% CI 0.94-1.6, P<0.00009) in ARDS patients. Increasing chest imaging opacities, plateau pressure, and clinician documentation of ARDS also were associated with lower tidal volume in ARDS patients. Our EHR-based data-driven approach using height, gender, ARDS documentation, and lowest standardized tidal volume yielded estimates of clinician ARDS recognition rates of 54% for mild, 63% for moderate, and 73% for severe ARDS. Our tool replicated clinician-reported ARDS recognition in the LUNG SAFE study, enabling the identification of ARDS patients at high risk of being unrecognized. Our approach can be generalized to other conditions for which there is a need to increase adoption of evidence-based care.

The first step is recognizing there is a problem: a methodology for adjusting for variability in disease severity when estimating clinician performance.

BACKGROUND: Adoption of innovations in the field of medicine is frequently hindered by a failure to recognize the condition targeted by the innovation. This is particularly true in cases where recognition requires integration of patient information from different sources, or where disease presentation can be heterogeneous and the recognition step may be easier for some patients than for others. METHODS: We propose a general data-driven metric for clinician recognition that accounts for the variability in patient disease severity and for institutional standards. As a case study, we evaluate the ventilatory management of 362 patients with acute respiratory distress syndrome (ARDS) at a large academic hospital, because clinician recognition of ARDS has been identified as a major barrier to adoption to evidence-based ventilatory management. We calculate our metric for the 48 critical care physicians caring for these patients and examine the relationships between differences in ARDS recognition performance from overall institutional levels and provider characteristics such as demographics, social network position, and self-reported barriers and opinions. RESULTS: Our metric was found to be robust to patient characteristics previously demonstrated to affect ARDS recognition, such as disease severity and patient height. Training background was the only factor in this study that showed an association with physician recognition. Pulmonary and critical care medicine (PCCM) training was associated with higher recognition (ß = 0.63, 95% confidence interval 0.46-0.80, p < 7 × 10- 5). Non-PCCM physicians recognized ARDS cases less frequently and expressed greater satisfaction with the ability to get the information needed for making an ARDS diagnosis (p < 5 × 10- 4), suggesting that lower performing clinicians may be less aware of institutional barriers. CONCLUSIONS: We present a data-driven metric of clinician disease recognition that accounts for variability in patient disease severity and for institutional standards. Using this metric, we identify two unique physician populations with different intervention needs. One population consistently recognizes ARDS and reports barriers vs one does not and reports fewer barriers.

Clinical and Biochemical Markers of Risk in Uncomplicated Severe Acute Malnutrition.

BACKGROUND AND OBJECTIVES: Use of mid-upper arm circumference (MUAC) as a single screening tool for severe acute malnutrition (SAM) assumes that children with a low weight-for-height z score (WHZ) and normal MUAC have lower risks of morbidity and mortality. However, the pathophysiology and functional severity associated with different anthropometric phenotypes of SAM have never been well characterized. We compared clinical characteristics, biochemical features, and health and nutrition histories of nonedematous children with SAM who had (1) low WHZ only, (2) both low WHZ and low MUAC, or (3) low MUAC only. METHODS: In Bangladesh, Burkina Faso, and Liberia, we conducted a multicentric cohort study in uncomplicated, nonedematous children with SAM and low MUAC only (n = 161), low WHZ only (n = 138), or a combination of low MUAC and low WHZ (n = 152). Alongside routine anthropometric measurements, we collected a wide range of critical indicators of clinical and nutritional status and viability; these included serum leptin, an adipocytokine negatively associated with mortality risk in SAM. RESULTS: Median leptin levels at diagnosis were lower in children with low WHZ only (215.8 pg/mL; P < .001) and in those with combined WHZ and MUAC deficits (180.1 pg/mL; P < .001) than in children with low MUAC only (331.50 pg/mL). The same pattern emerged on a wide range of clinical indicators, including signs of severe wasting, dehydration, serum ferritin levels, and caretaker-reported health deterioration, and was replicated across study sites. CONCLUSIONS: Illustrative of the likely heterogeneous functional severity of the different anthropometric phenotypes of SAM, our results confirm the need to retain low WHZ as an independent diagnostic criterion.

Promoting Evidence-Based Practice in Acute Respiratory Distress Syndrome: A Systematic Review.

Low tidal volume ventilation and prone positioning are recommended therapies yet underused in acute respiratory distress syndrome. We aimed to assess the role of interventions focused on implementation of low tidal volume ventilation and prone positioning in mechanically ventilated adult patients with acute respiratory distress syndrome. DATA SOURCES: PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: We searched the four databases from January 1, 2001, to January 28, 2021, for studies that met the predefined search criteria. Selected studies focused on interventions to improve implementation of low tidal volume ventilation and prone positioning in mechanically ventilated patients with acute respiratory distress syndrome. DATA EXTRACTION: Two authors independently performed study selection and data extraction using a standardized form. DATA SYNTHESIS: Due to methodological heterogeneity of included studies, meta-analysis was not feasible; thus, we provided a narrative summary and assessment of the literature. Eight nonrandomized studies met our eligibility criteria. Most studies looked at interventions to improve adherence to low tidal volume ventilation. Most interventions focused on education for providers. Studies were primarily conducted in the ICU and involved trainees, intensivists, respiratory therapists, and critical care nurses. Although overall quality of the studies was very low, the primary outcomes of interest suggest that interventions could improve adherence to or implementation of low tidal volume ventilation and prone positioning in acute respiratory distress syndrome. MEASUREMENTS AND MAIN RESULTS: Two authors independently performed study selection and data extraction using a standardized form. Due to methodologic heterogeneity of included studies, meta-analysis was not feasible; thus, we provided a narrative summary and assessment of the literature. Eight nonrandomized studies met our eligibility criteria. Most studies looked at interventions to improve adherence to low tidal volume ventilation. Most interventions focused on education for providers. Studies were primarily conducted in the ICU and involved trainees, intensivists, respiratory therapists, and critical care nurses. Although overall quality of the studies was very low, the primary outcomes of interest suggest that interventions could improve adherence to or implementation of low tidal volume ventilation and prone positioning in acute respiratory distress syndrome. CONCLUSIONS: There is a dearth of literature addressing interventions to improve implementation of evidence-based practices in acute respiratory distress syndrome. Existing interventions to improve clinician knowledge and facilitate application of low tidal volume ventilation and prone positioning may be effective, but supporting studies have significant limitations.

Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Rationale: Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy.Objectives: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine.Methods: The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines.Measurements and Main Results: There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when 1) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (replacement); 2) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (complementary); or 3) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "sequential").Conclusions: Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.

Long-term Overall Survival Outcomes in Patients with Early Stage, Peripherally Located, Non-small Cell Lung Cancer Treated with Stereotactic Ablative Radiotherapy in a Non-academic Cancer Centre.

AIMS: To report long-term outcomes of patients treated with stereotactic ablative radiotherapy (SABR) for early stage, peripherally located non-small cell lung cancer. MATERIALS AND METHODS: Data were collected retrospectively between September 2009 and May 2019. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. All patients were treated according to local protocol based on the national UK SABR Consortium guidelines. Risk-adapted treatment schedules were used depending on the size and the location of the tumour (54 Gy in three fractions, 55 Gy in five fractions, 60 Gy in eight fractions or 50 Gy in 10 fractions). Overall survival outcomes were evaluated using the Kaplan-Meier method. RESULTS: In total, 412 patients were included in the analysis. The median age was 76 years (range 48-93 years). Histological confirmation was obtained in 233 cases (56.6%). The median overall survival for all patients was 42.3 months (95% confidence interval 37.3-47.3 months), with 3- and 5-year overall survival of 52.8% and 37.3%, respectively. For biopsy-proven patients (56.6%), 3- and 5-year overall survival was 57.3% and 40.1%, respectively. With respect to overall survival, univariate and multivariate analysis revealed no significant difference in survival by technique (volume-modulated arc therapy versus conformal; three-dimensional computed tomography versus four-dimensional computed tomography), tumour location, smoking status at first contact, pre-treatment tumour stage or pre-treatment standardised uptake value. Survival was poorer for patients who received the 50 Gy in 10 fractions schedule. Treatment was very well tolerated with very low rates of grade 3-4 toxicity (1%). CONCLUSIONS: SABR for peripherally located, medically inoperable non-small cell lung cancer can be safely and effectively implemented in a non-academic institution with appropriate equipment and training. Overall survival outcomes and toxicity rates are comparable with internationally published studies. Patients treated with 50 Gy in 10 fractions had a poorer survival outcome.