Harnessing machine learning to predict cytochrome P450 inhibition through molecular properties.

Cytochrome P450 enzymes are a superfamily of enzymes responsible for the metabolism of a variety of medicines and xenobiotics. Among the Cytochrome P450 family, five isozymes that include 1A2, 2C9, 2C19, 2D6, and 3A4 are most important for the metabolism of xenobiotics. Inhibition of any of these five CYP isozymes causes drug-drug interactions with high pharmacological and toxicological effects. So, the inhibition or non-inhibition prediction of these isozymes is of great importance. Many techniques based on machine learning and deep learning algorithms are currently being used to predict whether these isozymes will be inhibited or not. In this study, three different molecular or substructural properties that include Morgan, MACCS and Morgan (combined) and RDKit of the various molecules are used to train a distinct SVM model against each isozyme (1A2, 2C9, 2C19, 2D6, and 3A4). On the independent dataset, Morgan fingerprints provided the best results, while MACCS and Morgan (combined) achieved comparable results in terms of balanced accuracy (BA), sensitivity (Sn), and Mathews correlation coefficient (MCC). For the Morgan fingerprints, balanced accuracies (BA), Mathews correlation coefficients (MCC), and sensitivities (Sn) against each CYPs isozyme, 1A2, 2C9, 2C19, 2D6, and 3A4 on an independent dataset ranged between 0.81 and 0.85, 0.61 and 0.70, 0.72 and 0.83, respectively. Similarly, on the independent dataset, MACCS and Morgan (combined) fingerprints achieved competitive results in terms of balanced accuracies (BA), Mathews correlation coefficients (MCC), and sensitivities (Sn) against each CYPs isozyme, 1A2, 2C9, 2C19, 2D6, and 3A4, which ranged between 0.79 and 0.85, 0.59 and 0.69, 0.69 and 0.82, respectively.

Demographic Attributes of Knowledge, Attitude, Practices, and One Health Perspective Regarding Diarrhea in Pakistan.

Background: Loose bowels is a clinical sign of gastrointestinal transport channel proteins, channels, and physical and chemical boundaries being harmed, prompting issues of water and electrolyte transport in the intestinal system. It is still considered as a major reason for emergency visits to hospitals in low-middle income countries. Zinc is a suitable treatment along with ORS for diarrhea. KAP surveys are usually conducted to collect information about general or specific topics of a particular population. The objective of this study was to investigate the knowledge, attitude, practices (KAP), and one health perspective regarding diarrhea among the participants from urban and rural populations of Rawalpindi and Islamabad, Pakistan. Methods: Data was collected by conducting a survey among residents of twin cities over a period of 6 months (from July 2020 to December 2020). The questionnaire compromised socio-demographic features and the degree of KAP with respect to diarrhea management and control. One way ANOVA tests were applied to observe the demographic relationship and various factors influencing knowledge, attitude, practices, and one health perspective about diarrhea. Results: A total of 338 subjects participated in the study. Female subjects were in the majority with 63% while the rest were male. A majority of the participants were between 15-25 years of age and 79.6% participants were un-married. The leading ethnic group was Punjabi with 52.7%; the lowest ethnic group were of Sindhi ethnicity with 8.6%. Age has a significant association with respect to knowledge and attitude. Religion has a significant association with respect to knowledge, practices, and one health, while education/qualification has an association with knowledge. The rest of the variables found no association with each other. Conclusion: It is concluded from the recent study that most residents of the twin cities of Pakistan knew about diarrhea and had a good attitude and practices toward it. Age, religion, and education have different roles regarding different diseases in the population of Pakistan. The current study has its limitations as well. Parts of the study were conducted in the capital of Pakistan which is more developed as compared to other areas of Pakistan. It would be better to explore the remote areas of Pakistan where basic amenities of life such as education, wealth, and unemployment are not available. It is important to create more awareness among community members. They should be aware how dangerous these viruses and bacteria can be. Other parts of Pakistan should also be explored for better understanding that will help in making a nationwide health policy.

Surveillance of molecular markers of antimalarial drug resistance in Plasmodium falciparum and Plasmodium vivax in Federally Administered Tribal Area (FATA), Pakistan.

This molecular epidemiological study was designed to determine the antimalarial drug resistance pattern, and the genetic diversity of malaria isolates collected from a war-altered Federally Administered Tribal Area (FATA), in Pakistan. Clinical isolates were collected from Bajaur, Mohmand, Khyber, Orakzai and Kurram agencies of FATA region between May 2017 and May 2018, and they underwent DNA extraction and amplification. The investigation of gene polymorphisms in drug resistance genes (dhfr, dhps, crt, and mdr1) of Plasmodium falciparum and Plasmodium vivax was carried out by pyrosequencing and Sanger sequencing, respectively. Out of 679 PCR-confirmed malaria samples, 523 (77%) were P. vivax, 121 (18%) P. falciparum, and 35 (5%) had mixed-species infections. All P. falciparum isolates had pfdhfr double mutants (C59R+S108N), while pfdhfr/pfdhps triple mutants (C59R+S108N+A437G) were detected in 11.5% of the samples. About 97.4% of P. falciparum isolates contained pfcrt K76T mutation, while pfmdr1 N86Y and Y184F mutations were present in 18.2% and 10.2% of the samples. P. vivax pvdhfr S58R mutation was present in 24.9% of isolates and the S117N mutation in 36.2%, while no mutation in the pvdhps gene was found. Pvmdr1 F1076L mutation was found in nearly all samples, as it was observed in 98.9% of isolates. No significant anti-folate and chloroquine resistance was observed in P. vivax; however, mutations associated with antifolate-resistance were found, and the chloroquine-resistant gene has been observed in 100% of P. falciparum isolates. Chloroquine and sulphadoxine-pyrimethamine resistance were found to be high in P. falciparum and low in P. vivax. Chloroquine could still be used for P. vivax infection but need to be tested in vivo, whereas a replacement of the artemisinin combination therapy for P. falciparum appears to be justified.

Assessment and prevalence of concomitant chemo-radiotherapy-induced oral mucositis in patients with oral squamous cell carcinoma

Background/aim: Quantification of oral mucositis that progresses during concomitant chemo-radiotherapy (CCRT) is essential for its management. It is important to determine the methods that are simple, reliable and beneficial in foreseeing mucositis at earlier stages of treatment. Materials and methods: A prospective study was conducted on 100 oral cancer patients receiving CCRT following the inclusion criteria. Patients were evaluated for mucositis i.e. erythema and ulcers by using the World Health Organization (WHO) scale and the oral mucositis assessment scale (OMAS), whereas mature and immature cells were identified by exfoliative cytology. Clinical examination and procedure of oral cavity were performed before, on days 5, 17, and at the end of treatment. Results: Oral mucositis was observed in all oral squamous cell carcinoma (OSCC) patients receiving CCRT on different days with noteworthy increase from day 5 of CCRT to the end of treatment. For OMAS grading related to ulceration and erythema, Grade 1 (7.2%; 34%) was most commonly seen on the 5th day of CCRT, Grade 2 (29%; 19%) and Grade 3 (19%) were most frequently seen at the 17th day and end of CCRT, accordingly. With respect to WHO scale grades 1 and 2 (18.3%; 21.5%) was most frequently observed at the 17th day of CCRT, whereas grades 3 and 4 (12.5%; 2%) was noted at the end of CCRT. There was statistically significant increase in the percentage of immature cells at the end of CCRT (99%). A significant association (P < 0.0000) was observed among the days of smear and maturation stages of epithelial cells as well as among WHO mucositis grading, OMAS and types of epithelial cells, respectively. Conclusion: According to the findings of the study, oral mucositis grade is directly proportional to the progressing days of CCRT. Oral mucositis is frequently related to adverse clinical outcomes, affecting the patient's quality of life. It is essential to develop methods that can be employed for the assessment of CCRT associated oral mucositis.