Prediction of Mortality in Very Premature Infants: A Systematic Review of Prediction Models

CONTEXT Being born very preterm is associated with elevated risk for neonatal mortality. The aim of this review is to give an overview of prediction models for mortality in very premature infants, assess their quality, identify important predictor variables, and provide recommendations for development of future models. METHODS Studies were included which reported the predictive performance of a model for mortality in a very preterm or very low birth weight population, and classified as development, validation, or impact studies. For each development study, we recorded the population, variables, aim, predictive performance of the model, and the number of times each model had been validated. Reporting quality criteria and minimum methodological criteria were established and assessed for development studies. RESULTS We identified 41 development studies and 18 validation studies. In addition to gestational age and birth weight, eight variables frequently predicted survival: being of average size for gestational age, female gender, non-white ethnicity, absence of serious congenital malformations, use of antenatal steroids, higher 5-minute Apgar score, normal temperature on admission, and better respiratory status. Twelve studies met our methodological criteria, three of which have been externally validated. Low reporting scores were seen in reporting of performance measures, internal and external validation, and handling of missing data. CONCLUSIONS Multivariate models can predict mortality better than birth weight or gestational age alone in very preterm infants. There are validated prediction models for classification and case-mix adjustment. Additional research is needed in validation and impact studies of existing models, and in prediction of mortality in the clinically important subgroup of infants where age and weight alone give only an equivocal prognosis.Stephanie Medlock, Anita C. J. Ravelli, Pieter Tamminga, Ben W. M. Mol, Ameen Abu-Hann

A systematic review on quality indicators for tight glycaemic control in critically ill patients: need for an unambiguous indicator reference subset

Introduction The objectives of this study were to systematically identify and summarize quality indicators of tight glycaemic control in critically ill patients, and to inspect the applicability of their definitions. Methods We searched in MEDLINE (R) for all studies evaluating a tight glycaemic control protocol and/or quality of glucose control that reported original data from a clinical trial or observational study on critically ill adult patients. Results Forty-nine studies met the inclusion criteria; 30 different indicators were extracted and categorized into four nonorthogonal categories: blood glucose zones (for example, 'hypoglycaemia'); blood glucose levels (for example, 'mean blood glucose level'); time intervals (for example, 'time to occurrence of an event'); and protocol characteristics (for example, 'blood glucose sampling frequency'). Hypoglycaemia-related indicators were used in 43 out of 49 studies, acting as a proxy for safety, but they employed many different definitions. Blood glucose level summaries were used in 41 out of 49 studies, reported as means and/or medians during the study period or at a certain time point (for example, the morning blood glucose level or blood glucose level upon starting insulin therapy). Time spent in the predefined blood glucose level range, time needed to reach the defined blood glucose level target, hyperglycaemia-related indicators and protocol-related indicators were other frequently used indicators. Most indicators differ in their definitions even when they are meant to measure the same underlying concept. More importantly, many definitions are not precise, prohibiting their applicability and hence the reproducibility and comparability of research results. Conclusions An unambiguous indicator reference subset is necessary. The result of this systematic review can be used as a starting point from which to develop a standard list of well defined indicators that are associated with clinical outcomes or that concur with clinicians' subjective views on the quality of the regulatory proces

Using HAQ-DI to estimate HUI-3 and EQ-5D utility values for patients with rheumatoid arthritis in Spain

AbstractBackground/ObjectiveUtility values are not usually assessed in clinical trials and do not allow cost-utility analysis to be performed with the data collected. The aim of this study was to derive relation functions so that Health Assessment Questionnaire – Disability Index (HAQ-DI) scores could be used to estimate Health Utilities Index - 3 (HUI-3) and EQ-5D utility values for patients with rheumatoid arthritis (RA).MethodsAn observational, cross-sectional, naturalistic, multicentre study was conducted. A total of 244 patients aged 18 years or older, with RA according to American College of Rheumatology diagnostic criteria, were recruited. Sociodemographic and clinical variables were recorded and patients completed three generic HRQoL questionnaires: the HAQ-DI, the HUI-3, and the EQ-5D. Two linear regression models were used to predict HUI-3 and EQ-5D utility values as functions of HAQ-DI scores, age, and gender.ResultsPatient mean age was 57.8 years old (standard deviation [SD], 13.3 years); 75.8% of the patients were women and 95.9% were white. Mean disease duration was 10.8 years (SD, 9 years). Patient distribution according to HAQ-DI severity was as follows: HAQ-DI < 0.5, 29%; 0.5 ≤ HAQ-DI < 1.1, 28%; 1.1 ≤ HAQ-DI < 1.6, 16%,1.6 ≤ HAQ-DI < 2.1, 15%; and HAQ-DI ≥ 2.1, 12%. HAQ-DI and EQ-5D mean scores were 1.02 (SD, 0.78) and 63.1 (SD, 20.3), respectively. Mean utility values for HUI-3 and time trade-off (TTO) were 0.75 (SD, 0.21) and 0.65 (SD, 0.3), respectively. The equations converting HAQ-DI scores to utilities were HUI-3 = 0.9527 – (0.2018 × HAQ-DI) +ε (R2=0.56), and TTO = 0.9567 – (0.309 × HAQ-DI) + ε (R2=0.54). Error distribution was non-normal. Age and gender were found to have no bearing on the utility functions.ConclusionsHAQ-DI scores can be used to estimate HUI-3 and EQ-5D utility values for patients with RA in data obtained from studies where utility values have not been collected

Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin

Adipose-derived stem cells (ADSCs) as part of autologous fat grafting have anti-fibrotic and anti-inflammatory effects, but the exact mechanisms of action remain unknown. By simulating the interaction of ADSCs with fibroblasts and endothelial cells (EC) from scleroderma (SSc) skin in silico, we aim to unravel these mechanisms. Publicly available single-cell RNA sequencing data from the stromal vascular fraction of 3 lean patients and biopsies from the skin of 10 control and 12 patients with SSc were obtained from the GEO and analysed using R and Seurat. Differentially expressed genes were used to compare the fibroblast and EC transcriptome between controls and SSc. GO and KEGG functional enrichment was performed. Ligand–receptor interactions of ADSCs with fibroblasts and ECs were explored with LIANA. Pro-inflammatory and extracellular matrix (ECM) interacting fibroblasts were identified in SSc. Arterial, capillary, venous and lymphatic ECs showed a pro-fibrotic and pro-inflammatory transcriptome. Most interactions with both cell types were based on ECM proteins. Differential interactions identified included NTN1, VEGFD, MMP2, FGF2, and FNDC5. The ADSC secretome may disrupt vascular and perivascular inflammation hubs in scleroderma by promoting angiogenesis and especially lymphangiogenesis. Key phenomena observed after fat grafting remain unexplained, including modulation of fibroblast behaviour

The Role of the K2P Channels TASK-1, TREK-1 and TREK-2 in the Use of Treprostinil Therapy in Pulmonary Arterial Hypertension

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease affecting ~6 people per million, per year (1). Recent studies have reported mutations in the two-pore domain potassium (K2P) channel TASK-1 (KCNK3) giving rise to PAH (2). Treprostinil is a stable prostacyclin analogue often administered as a therapy in PAH, to keep blood vessels open. Its mode of action is thought to occur through an interaction with prostanoid receptors, DP₂, EP₂ and IP (3). Patients undergoing continuous subcutaneous treprostinil infusion can often exhibit severe pain at the site of delivery (4). In this study we investigate the action of treprostinil on TASK-1 and on two other K2P channels, TREK-1 (KCNK2) and TREK-2 (KCNK10), which regulate the excitability of sensory neurons and are implicated in pain (5). METHOD: Using the whole-cell patch-clamp technique, currents were measured through human TASK-1, TREK-1 and TREK-2 channels transiently expressed in tsA-201 cells. TASK-1 was also co-expressed with prostanoid receptors (IP, DP₂ and EP₂). Data are expressed as mean ± SEM (n = cells) of current measured at −40 mV and mean % change ± SEM (n = cells), with statistical analysis performed using a paired t-test. RESULTS: Acute application of treprostinil (1 μM) on cells expressing TASK-1 channels had no effect on current (control: 234 ± 80 pA; treprostinil: 240 ± 53 pA, n = 5, p > 0.05). Co-expression of TASK-1 with various prostanoid receptors, followed by acute application of treprostinil (1 μM) resulted in varying effects on TASK-1 current. In cells expressing WT TASK-1 and IP receptors, the average TASK-1 current significantly decreased by 50% in the presence of treprostinil (control: 333 ± 82 pA; treprostinil (1 μM): 173 ± 46 pA, n = 6, p 0.05). Interestingly, treprostinil had a potent inhibitory effect on TREK-1 (80 ± 8%, n = 5, p < 0.05) and TREK-2 channels (59 ± 9%, n = 5, p < 0.05) in the absence of prostanoid receptors. CONCLUSION: In this study, acutely applied treprostinil did not appear to have a direct action on the TASK-1 channels, themselves, instead its effects appeared to occur through the activation of prostanoid receptors and their associated signalling pathways. Conversely, treprostinil demonstrated a direct inhibitory effect on TREK-1 and TREK-2 channels. This effect of treprostinil may explain infusion site pain, a common side-effect of patients on subcutaneous treatment (4). Acute enhancement of TREK channel activity at the infusion site could therefore help to reduce discomfort in PAH patients

Interaction between geriatric syndromes in predicting three months mortality risk

Objectives: Capturing frailty using a quick tool has proven to be challenging. We hypothesise that this is due to the complex interactions between frailty domains. We aimed to identify these interactions and assess whether adding interactions between domains improves mortality predictability. Methods: In this retrospective cohort study, we selected all patients aged 70 or older who were admitted to one Dutch hospital between April 2015 and April 2016. Patient characteristics, frailty screening (using VMS (Safety Management System), a screening tool used in Dutch hospital care), length of stay, and mortality within three months were retrospectively collected from electronic medical records. To identify predictive interactions between the frailty domains, we constructed a classification tree with mortality as the outcome using five variables: the four VMS-domains (delirium risk, fall risk, malnutrition, physical impairment) and their sum. To determine if any domain interactions were predictive for three-month mortality, we performed a multivariable logistic regression analysis. Results: We included 4,478 patients. (median age: 79 years; maximum age: 101 years; 44.8% male) The highest risk for three-month mortality included patients that were physically impaired and malnourished (23% (95%-CI 19.0–27.4%)). Subgroups had comparable three-month mortality risks based on different domains: malnutrition without physical impairment (15.2% (96%-CI 12.4–18.6%)) and physical impairment and delirium risk without malnutrition (16.3% (95%-CI 13.7–19.2%)). Discussion: We showed that taking interactions between domains into account improves the predictability of three-month mortality risk. Therefore, when screening for frailty, simply adding up domains with a cut-off score results in loss of valuable information

Interaction between geriatric syndromes in predicting three months mortality risk

Objectives: Capturing frailty using a quick tool has proven to be challenging. We hypothesise that this is due to the complex interactions between frailty domains. We aimed to identify these interactions and assess whether adding interactions between domains improves mortality predictability. Methods: In this retrospective cohort study, we selected all patients aged 70 or older who were admitted to one Dutch hospital between April 2015 and April 2016. Patient characteristics, frailty screening (using VMS (Safety Management System), a screening tool used in Dutch hospital care), length of stay, and mortality within three months were retrospectively collected from electronic medical records. To identify predictive interactions between the frailty domains, we constructed a classification tree with mortality as the outcome using five variables: the four VMS-domains (delirium risk, fall risk, malnutrition, physical impairment) and their sum. To determine if any domain interactions were predictive for three-month mortality, we performed a multivariable logistic regression analysis. Results: We included 4,478 patients. (median age: 79 years; maximum age: 101 years; 44.8% male) The highest risk for three-month mortality included patients that were physically impaired and malnourished (23% (95%-CI 19.0–27.4%)). Subgroups had comparable three-month mortality risks based on different domains: malnutrition without physical impairment (15.2% (96%-CI 12.4–18.6%)) and physical impairment and delirium risk without malnutrition (16.3% (95%-CI 13.7–19.2%)). Discussion: We showed that taking interactions between domains into account improves the predictability of three-month mortality risk. Therefore, when screening for frailty, simply adding up domains with a cut-off score results in loss of valuable information.</p