A flexible symbolic regression method for constructing interpretable clinical prediction models.

Machine learning (ML) models trained for triggering clinical decision support (CDS) are typically either accurate or interpretable but not both. Scaling CDS to the panoply of clinical use cases while mitigating risks to patients will require many ML models be intuitively interpretable for clinicians. To this end, we adapted a symbolic regression method, coined the feature engineering automation tool (FEAT), to train concise and accurate models from high-dimensional electronic health record (EHR) data. We first present an in-depth application of FEAT to classify hypertension, hypertension with unexplained hypokalemia, and apparent treatment-resistant hypertension (aTRH) using EHR data for 1200 subjects receiving longitudinal care in a large healthcare system. FEAT models trained to predict phenotypes adjudicated by chart review had equivalent or higher discriminative performance (p < 0.001) and were at least three times smaller (p < 1 × 10-6) than other potentially interpretable models. For aTRH, FEAT generated a six-feature, highly discriminative (positive predictive value = 0.70, sensitivity = 0.62), and clinically intuitive model. To assess the generalizability of the approach, we tested FEAT on 25 benchmark clinical phenotyping tasks using the MIMIC-III critical care database. Under comparable dimensionality constraints, FEAT's models exhibited higher area under the receiver-operating curve scores than penalized linear models across tasks (p < 6 × 10-6). In summary, FEAT can train EHR prediction models that are both intuitively interpretable and accurate, which should facilitate safe and effective scaling of ML-triggered CDS to the panoply of potential clinical use cases and healthcare practices.

Stress Response of European Common Frog (Rana temporaria) Tadpoles to Bti Exposure in an Outdoor Pond Mesocosm.

The biocide Bacillus thuringiensis var. israelensis (Bti) is applied to wetlands to control nuisance by mosquitoes. Amphibians inhabiting these wetlands can be exposed to Bti multiple times, potentially inducing oxidative stress in developing tadpoles. For biochemical stress responses, ambient water temperature plays a key role. Therefore, we exposed tadpoles of the European common frog (Rana temporaria) three times to field-relevant doses of Bti in outdoor floodplain pond mesocosms (FPM) under natural environmental conditions. We sampled tadpoles after each Bti application over the course of a 51-day experiment (April to June 2021) and investigated the activity of the glutathione-S-transferase (GST) and protein carbonyl content as a measure for detoxification activity and oxidative damage. GST activity increased over the course of the experiment likely due to a general increase of water temperature. We did not observe an effect of Bti on either of the investigated biomarkers under natural ambient temperatures. However, Bti-induced effects may be concealed by the generally low water temperatures in our FPMs, particularly at the first application in April, when we expected the highest effect on the most sensitive early stage tadpoles. In light of the global climate change, temperature-related effects of pesticides and biocides on tadpoles should be carefully monitored - in particular since they are known as one of the factors driving the worldwide decline of amphibian populations.

Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis.

Interleukin-33 (IL-33) acts as an 'alarmin', and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT.

Camptothecin encapsulated into functionalized MCM-41: In vitro release study, cytotoxicity and kinetics.

The application of MCM-41 functionalized by 12-tungstophosphoric acid (TPA) as drug carrier for cancer treatment was studied by loading of camptothecin (CPT). In-vitro controlled release study of CPT in Simulated Body Fluid (pH 7.4, 37 °C) was carried out under stirring as well as static conditions. The systems were also evaluated on cancer cells (HepG2) and the carriers are found to be non-toxic to the cancer cells. In order to see the influence of inorganic moiety on release rate of drug, study was also carried out with CPT loaded unfunctionalized MCM-41. A detailed study on release kinetics and release mechanism using First Order Release Kinetic Model, Higuchi Model, Koresmeyer-Pepps Model and Extended kinetic model was also carried out.

Publication rate of scientific papers presented at the XXVI Annual Convention of National Neonatology Forum (NEOCON 2006).

OBJECTIVES: To document the publication rate of papers presented at the Annual Convention of National Neonatology Forum of India (NNF), and study the factors associated with their subsequent publication. METHODS: All papers presented at the NEOCON 2006, the XXVI annual convention of NNF at Varanasi, India, were searched for subsequent full publication, by an internet-based search using Pubmed, Google Scholar and Indmed. Publication of the presented paper was looked for in English language, peer-reviewed, indexed journals over the next five years (1st January 2007 to 31st December, 2011). The full published papers were compared with the abstract and differences noted. RESULTS: One hundred and two papers and posters were presented at the conference and 14 (13.7 %) of these were published in the next five years. None was published in any un-indexed journal. The highest percentage of paper publication was from the Award paper category (83.3 %) and least from Innovation category (none). The only factor significantly associated with subsequent publication was presentation as an Award paper (P < 0.001). On comparison of the presented abstracts and the published papers, there was a change in authors in 78.5 %, title in 42.8 %, and the data in 35.7 %. CONCLUSIONS: The subsequent publication of conference abstracts as a full-paper is sub-optimal in the field of neonatology. Further research is needed to identify the factors responsible for the poor subsequent publication, and efforts need to be made to address them both at the institutional and the researchers' level.