A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine.

SummaryAdvances in the field of pharmacogenomics have resulted in the discovery of some important single‐nucleotide polymorphisms which are found to be associated with opioid dose variability. This, to a large extent, explains genetic variability in the analgesic dose of opioids. These polymorphisms are found in various areas relevant to pain perception, including the nociceptive and antinociceptive pathways, drug receptors, drug‐metabolising enzymes and drug efflux molecules. An in‐depth knowledge of single‐nucleotide polymorphisms can help clinicians to address interindividual variability in opioid dosing and requirements. In the era of precision medicine, these genetic markers can also help us to design prognostic tools to accurately predict the analgesic dose of opioids.

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Fentanyl exhibits interindividual variability in its dose requirement due to various nongenetic and genetic factors such as single nucleotide polymorphisms (SNPs). This study aims to develop and cross-validate robust predictive models for postoperative fentanyl analgesic requirement and other related outcomes in patients undergoing major breast surgery. Data regarding genotypes of 10 candidate SNPs, cold pain test (CPT) scores, pupillary response to fentanyl (PRF), and other common clinical characteristics were recorded from 257 patients undergoing major breast surgery. Predictive models for 24-hour fentanyl requirement, 24-hour pain scores, and time for first analgesic (TFA) in the postoperative period were developed using 4 different algorithms: generalised linear regression model, linear support vector machine learning (SVM-Linear), random forest (RF), and Bayesian regularised neural network. The variant genotype of OPRM1 (rs1799971) and higher CPT scores were associated with higher 24-hour postoperative fentanyl consumption, whereas higher PRF and history of hypertension were associated with lower fentanyl requirement. The variant allele of COMT (rs4680) and higher CPT scores were associated with 24-hour postoperative pain scores. The variant genotype of CTSG (rs2070697), higher intraoperative fentanyl use, and higher CPT scores were associated with significantly lower TFA. The predictive models for 24-hour postoperative fentanyl requirement, pain scores, and TFA had R-squared values of 0.313 (SVM-Linear), 0.434 (SVM-Linear), and 0.532 (RF), respectively. We have developed and cross-validated predictive models for 24-hour postoperative fentanyl requirement, 24-hour postoperative pain scores, and TFA with satisfactory performance characteristics and incorporated them in a novel web application.

Background A national drug resistance survey (DRS) was implemented for the first time in Timor-Leste (TL) in 2019. The primary objective of the survey was to assess the prevalence of drug resistance among new and previously treated pulmonary TB patients in the country. Methods This nation-wide cross-sectional survey was conducted in 2019 targeting all new and previously treated sputum smear-positive pulmonary TB patients. Sputum samples were submitted to the National TB Reference Laboratory for confirmation of TB and to determine resistance to rifampicin by Xpert MTB/RIF. Culture was performed on solid media, and culture isolates of confirmed TB cases were shipped to the WHO Supranational TB Reference Laboratory in Chennai, India for whole genome sequencing (WGS). Survey summary statistics, data cross-tabulations and analysis of potential risk factors of rifampicin-resistant TB (RR-TB) were conducted using R statistical software (version 3.5.2). Results A total of 953 sputum-smear positive patients were enrolled, of which 917 were confirmed as positive for TB by either Xpert MTB/RIF or culture. An electronic web-based system was used for entry and storage of the data. Rifampicin resistance was detected among 0.6% (95% CI 0.2–1.3) of new cases and 2.7% (95% CI 0.5- 8.2) of previously treated cases. WGS was conducted for validation purposes on 65 randomly selected isolates (29% of RR-TB (2/7) and 7% of RS-TB (63/910) by Xpert MTB/RIF or pDST). The original test results agreed with the WGS validation results for 62/64 isolates (97%). Conclusion The prevalence of RR-TB in Timor-Leste is relatively low compared to the estimated proportions of RR-TB in the WHO South-East Asia Region (2.5% [95% CI 1.9–3.3] among new cases and 14% [95% CI 7.7–21] among previously treated cases). The rapid sputum collection and transportation mechanism implemented in the survey demonstrates its feasibility in low resource settings and should be replicated for routinely transporting TB specimens from microscopy labs to GeneXpert sites. Establishment of in-country capacity for rapid molecular diagnostics for both first- and second-line DST is an immediate need for achieving universal drug susceptibility testing (DST) to guide appropriate patient management.