AI Enabled Drug Design and Side Effect Prediction Powered by Multi-Objective Evolutionary Algorithms & Transformer Models

Due to the large search space and conflicting objectives, drug design and discovery is a difficult problem for which new machine learning (ML) approaches are required. Here, the problem is to invent a method by which new, therapeutically useful, compounds can be discovered; and to simultaneously avoid compounds which will fail clinical trials or pass unwanted effects onto the end patient. By extending current technologies as well as adding new ones, more design criteria can be included, and more promising novel drugs can be discovered. This work advances the field of computational drug design by (1) developing MOEA-DT, a non-deep learning application for multi-objective molecular optimization, which generates new molecules with high performance in a variety of design criteria; and (2) developing SEMTL-BERT, a side effect prediction algorithm which leverages the latest ML techniques and datasets to accomplish its task. Experiments performed show that MOEA-DT either matches or outperforms other similar methods, and that SEMTL-BERT can enhance predictive ability

Acil servise nefes darlığı ile başvuran hastaların arter kan gazı değerlerinin noninvaziv yöntemle ölçülen kan gazı değerleri ile karşılaştırılması

Çalışmamızda nefes darlığı ile başvuran hastalarda invaziv (arter) ve non-invaziv (transkütan) kan gazı sonuçlarını karşılaştırarak, non invaziv kan gazı ölçümünün klinik kullanıma uygunluğunun belirlenmesi amaçlandı. Çalışmamızda dispne sebebiyle acil servise başvuran ve arteryel kan gazı çalışılan 234 hasta dahil edildi. Hastaların tensor Tip MTX-Matrix cihazı ile parmak ucu sPO2, PO2, PCO2 ve pH değerleri ölçülerek arteryel kan gazı ile karşılaştırıldı. Sürekli verilerin normal dağılımının test edilmesinde Kolmogorov Smirnov testi kullanıldı. Grupların karşılaştırılmasında Mann Whitney U testi kullanıldı. İnvaziv (arter) ve non-invaziv (transkütan) kan gazı sonuçlarının uyumunu test etmede Bland Altman testi kullanıldı. Sonuçlar % 95’lik güven aralığında, anlamlılık p<0.05 düzeyinde değerlendirildi. Çalışmamızda 234 hastanın yaş ortalaması 69,0±18,1 yıl olup, hastaların%42,7’si erkekti. Hastalarda dispne dışında belirlenen en sık semptom göğüs ağrısı, en sık saptanan tanı pnömoniydi. Arter kan gazı (AKG) ölçülen pH yerine, transkütan pH kullanılabileceği saptandı (p>0,05). AKG’de ölçülen PCO2, PO2 ve sPO2’nin yerine, transkütan PCO2, PO2 ve sPO2 kullanılamayacağı saptandı (p0,05); AKG’deki PCO2 ve sPO2’nin yerine ve transkütan PCO2 ve sPO2’nin kullanılamayacağı saptandı (p>0,05). Akciğer patolojisi, kardiyak patolojisi ve enfeksiyon varlığı olan hastalarda; AKG’deki pH yerine transkütan pH kullanılabilirken (p>0,05); arteryel PO2, PCO2 ve sPO2’nin yerine transkütan PO2, PCO2 ve sPO2’nin kullanılamayacağı saptandı (p<0,05). Sonuç olarak transkütan olarak kan gazı parametrelerini değerlendirilen cihazlar dispneik hastalarda pH yerine kullanılabilir. Tüm kan gazı parametrelerinin değerlendirilmesi için cihazın geliştirilmesi gerekmektedir. We aimed to determine the suitability of non-invasive blood gas measurement for clinical use by comparing the results of invasive (arterial) and non-invasive (transcutaneous) blood gases in patients with dyspnea in our study. In our study, 234 patients were included who referred to emergency services due to dyspnea and whose arterial blood gas were measured. Tensor Type MTX-Matrix device was used to measure patients' fingertip sPO2, PO2, PCO2 and pH values and these values were compared with arterial blood gases. Kolmogorov Smirnov test was used to test the normal distribution of continuous data. The Mann Whitney-U test was used to compare groups.The Bland Altman test was used to test the compatibilitiy of invasive (arterial) and non-invasive (transcutaneous) blood gas results. The results were evaluated in a confidence interval of 95% and a significance level of p <0.05. The mean age of 234 patients in our study was 69.0 ± 18.1 years and 42.7% of the patients were male. The most frequent symptom except for dyspnea was chest pain, the most common diagnosis was pneumonia. It was determined that transcutaneous pH could be used instead of pH measured in arterial blood gas (ABG) (p> 0.05). It was found that, transcutaneous PCO2, PO2 and sPO2 could not be used instead ofPCO2, PO2 and sPO2level measured in ABG(p 0.05), it was found that transcutaneous PCO2 and sPO2 could not be used instead ofPCO2 and sPO2 in ABG (p> 0.05). In patients with lung pathology, cardiac pathology and infection; while transcutaneous pH could be used in place of the pH in AKG (p> 0.05); transcutaneous PO2, PCO2 and sPO2 could not be used instead of arterial PO2, PCO2 and sPO2 (p <0.05). As a result, devices that evaluate blood gas parameters as transcutaneously can be used instead of pH in dyspneic patients. For the evaluation of all blood gas parameters, the device needs to be improved

The role of ambulatory oxygen to improve skeletal muscle gene expression in Chronic Obstructive Pulmonary Disease in patients with exercise induced hypoxaemia

Rationale: Hypoxaemia plays a role in the aetiology of abnormal skeletal muscle function in Chronic obstructive pulmonary disease (COPD) via abnormal protein synthesis and mitochondrial function. Patients exhibiting exercise-induced desaturation (EID) have exercise intolerance, perhaps a consequence of muscle hypoxia. Ambulatory oxygen therapy (AOT) is indicated in these patients; however the evidence is derived from single assessment studies. This thesis explores the role of longer term AOT and whether it favourably alters skeletal muscle gene expression in patients with COPD and EID. Methods: A 12 week randomised controlled trial of AOT against air in 25 patients with COPD and EID was undertaken. Participants underwent skeletal muscle biopsies and exercise assessments. In parallel a systematic review of published literature from 1980-2014 for trials in which AOT was compared to placebo in COPD was completed. Results: The systematic review showed that AOT had no statistical effect on improving exercise capacity (6 minute walk or endurance shuttle walk tests); p=0.44 and p=0.29 respectively. Gene set enrichment analysis show the KEGG pathways of oxidative phosphorylation, PPAR signalling and fatty acid metabolism to be up-regulated following AOT (q<2%) in the clinical trial of AOT versus Air. Conclusion: AOT has limited long term benefit in improving functional exercise capacity. It may however favourably alter gene expression in patients with COPD and EID

Mechanical Ventilation

The therapeutic alliance has been found to predict psychotherapy outcome in numerous studies. However, critics maintain that the therapeutic alliance is a by-product of prior symptomatic improvements. Moreover, almost all alliance research to date has used differences between patients in alliance as predictor of outcome, and results of such analyses do not necessarily mean that improving the alliance with a given patient will improve outcome (i.e., a within-patient effect). In a sample of 646 patients (76% women, 24% men) in primary care psychotherapy, the effect of working alliance on next session symptom level was analyzed using multilevel models. The Clinical Outcomes in Routine Evaluation–Outcome Measure was used to measure symptom level, and the patient version of the Working Alliance Inventory–Short form revised (Hatcher &amp; Gillaspy, 2006) was used to measure alliance. There was evidence for a reciprocal causal model, in which the alliance predicted subsequent change in symptoms while prior symptom change also affected the alliance. The alliance effect varied considerably between patients. This variation was partially explained by patients with personality problems showing stronger alliance effect. These results indicate that the alliance is not just a by-product of prior symptomatic improvements, even though improvement in symptoms is likely to enhance the alliance. Results also point to the importance of therapists paying attention to ruptures and repair of the therapy alliance. Generalization of results may be limited to relatively brief primary care psychotherapy

Acute lung injury in paediatric intensive care: course and outcome

Introduction: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) carry a high morbidity and mortality (10-90%). ALI is characterised by non-cardiogenic pulmonary oedema and refractory hypoxaemia of multifactorial aetiology [1]. There is limited data about outcome particularly in children. Methods This retrospective cohort study of 85 randomly selected patients with respiratory failure recruited from a prospectively collected database represents 7.1% of 1187 admissions. They include those treated with High Frequency Oscillation Ventilation (HFOV). The patients were admitted between 1 November 1998 and 31 October 2000. Results: Of the 85, 49 developed acute lung injury and 47 had ARDS. There were 26 males and 23 females with a median age and weight of 7.7 months (range 1 day-12.8 years) and 8 kg (range 0.8-40 kg). There were 7 deaths giving a crude mortality of 14.3%, all of which fulfilled the Consensus I [1] criteria for ARDS. Pulmonary occlusion pressures were not routinely measured. The A-a gradient and PaO2/FiO2 ratio (median + [95% CI]) were 37.46 [31.82-43.1] kPa and 19.12 [15.26-22.98] kPa respectively. The non-survivors had a significantly lower PaO2/FiO2 ratio (13 [6.07-19.93] kPa) compared to survivors (23.85 [19.57-28.13] kPa) (P = 0.03) and had a higher A-a gradient (51.05 [35.68-66.42] kPa) compared to survivors (36.07 [30.2-41.94]) kPa though not significant (P = 0.06). Twenty-nine patients (59.2%) were oscillated (Sensormedics 3100A) including all 7 non-survivors. There was no difference in ventilation requirements for CMV prior to oscillation. Seventeen of the 49 (34.7%) were treated with Nitric Oxide including 5 out of 7 non-survivors (71.4%). The median (95% CI) number of failed organs was 3 (1.96-4.04) for non-survivors compared to 1 (0.62-1.62) for survivors (P = 0.03). There were 27 patients with isolated respiratory failure all of whom survived. Six (85.7%) of the non-survivors also required cardiovascular support.Conclusion: A crude mortality of 14.3% compares favourably to published data. The A-a gradient and PaO2/FiO2 ratio may be of help in morbidity scoring in paediatric ARDS. Use of Nitric Oxide and HFOV is associated with increased mortality, which probably relates to the severity of disease. Multiple organ failure particularly respiratory and cardiac disease is associated with increased mortality. ARDS with isolated respiratory failure carries a good prognosis in children

Wearable in-ear pulse oximetry: theory and applications

Wearable health technology, most commonly in the form of the smart watch, is employed by millions of users worldwide. These devices generally exploit photoplethysmography (PPG), the non-invasive use of light to measure blood volume, in order to track physiological metrics such as pulse and respiration. Moreover, PPG is commonly used in hospitals in the form of pulse oximetry, which measures light absorbance by the blood at different wavelengths of light to estimate blood oxygen levels (SpO2). This thesis aims to demonstrate that despite its widespread usage over many decades, this sensor still possesses a wealth of untapped value. Through a combination of advanced signal processing and harnessing the ear as a location for wearable sensing, this thesis introduces several novel high impact applications of in-ear pulse oximetry and photoplethysmography. The aims of this thesis are accomplished through a three pronged approach: rapid detection of hypoxia, tracking of cognitive workload and fatigue, and detection of respiratory disease. By means of the simultaneous recording of in-ear and finger pulse oximetry at rest and during breath hold tests, it was found that in-ear SpO2 responds on average 12.4 seconds faster than the finger SpO2. This is likely due in part to the ear being in close proximity to the brain, making it a priority for oxygenation and thus making wearable in-ear SpO2 a good proxy for core blood oxygen. Next, the low latency of in-ear SpO2 was further exploited in the novel application of classifying cognitive workload. It was found that in-ear pulse oximetry was able to robustly detect tiny decreases in blood oxygen during increased cognitive workload, likely caused by increased brain metabolism. This thesis demonstrates that in-ear SpO2 can be used to accurately distinguish between different levels of an N-back memory task, representing different levels of mental effort. This concept was further validated through its application to gaming and then extended to the detection of driver related fatigue. It was found that features derived from SpO2 and PPG were predictive of absolute steering wheel angle, which acts as a proxy for fatigue. The strength of in-ear PPG for the monitoring of respiration was investigated with respect to the finger, with the conclusion that in-ear PPG exhibits far stronger respiration induced intensity variations and pulse amplitude variations than the finger. All three respiratory modes were harnessed through multivariate empirical mode decomposition (MEMD) to produce spirometry-like respiratory waveforms from PPG. It was discovered that these PPG derived respiratory waveforms can be used to detect obstruction to breathing, both through a novel apparatus for the simulation of breathing disorders and through the classification of chronic obstructive pulmonary disease (COPD) in the real world. This thesis establishes in-ear pulse oximetry as a wearable technology with the potential for immense societal impact, with applications from the classification of cognitive workload and the prediction of driver fatigue, through to the detection of chronic obstructive pulmonary disease. The experiments and analysis in this thesis conclusively demonstrate that widely used pulse oximetry and photoplethysmography possess a wealth of untapped value, in essence teaching the old PPG sensor new tricks.Open Acces

Front Lines of Thoracic Surgery

Front Lines of Thoracic Surgery collects up-to-date contributions on some of the most debated topics in today's clinical practice of cardiac, aortic, and general thoracic surgery,and anesthesia as viewed by authors personally involved in their evolution. The strong and genuine enthusiasm of the authors was clearly perceptible in all their contributions and I'm sure that will further stimulate the reader to understand their messages. Moreover, the strict adhesion of the authors' original observations and findings to the evidence base proves that facts are the best guarantee of scientific value. This is not a standard textbook where the whole discipline is organically presented, but authors' contributions are simply listed in their pertaining subclasses of Thoracic Surgery. I'm sure that this original and very promising editorial format which has and free availability at its core further increases this book's value and it will be of interest to healthcare professionals and scientists dedicated to this field