A critical goal of lead compound selection and optimization is to maximize target engagement whilst minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition state destabilization rather than ground state stabilization. In the present work, we have evaluated the inhibition of InhA by 14 triazole-based diphenyl ethers and used a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship (SKR) for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to three orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.

Background Antiretroviral therapy (ART) regimens that contain Dolutegravir (DTG) have been associated with increases in body mass index (BMI) in adults. However, this relationship has not been well described in adolescents. Methods In a retrospective observational cohort of 460 virally suppressed (< 200 copies/ml) adolescents living with HIV at a clinical site in Eswatini, body mass index (BMI) measurements were analyzed between 1 year prior to the transition to DTG and up to 1 year after DTG transition. Random-effects linear spline models were used to describe the rate of change in BMI before and after the transition to DTG. Results In adolescents BMI increased at a rate of 0.3 kg/m 2 per year before DTG transition and increased to a rate of 1.2 kg/m 2 per year after DTG transition. Sex of the adolescent modified the relationship between DTG and rate of BMI change; BMI rate of change was increased by 1.1 kg/m 2 in females and 0.6 kg/m 2 per year after DTG transition in males. Conclusions Transition to DTG in virally suppressed adolescents, age 10 to 19, is associated with an increase in the rate of BMI change. Female adolescents may experience a larger change than males. Further investigation is required to elucidate the mechanism that underlies these observations and to assess how DTG impacts BMI in adolescents following longer durations of treatment.

Background Cancellations of elective surgeries on the day of surgery (DOS) can lead to added financial burden and wastage of resources for healthcare facilities; as well as social and emotional problems to patients. These cancellations act as barriers to delivering efficient surgical services. Optimal utilisation of the available resources is necessary for resource-constrained low-and-middle-income countries (LMIC). This study investigates the rate and causes of cancellations of elective surgeries on the DOS in various surgical departments across ten hospitals in India. Methods A research consortium ‘IndSurg’ led by World Health Organisation Collaboration Centre (WHOCC) for Research in Surgical Care Delivery in LMICs, India conducted this multicentre retrospective cross-sectional study to analyse the cancellations of elective/planned surgical operations on DOS across urban secondary and tertiary level hospitals. We audited surgical records of a pre-decided period of six weeks for cancellations, documented relevant demographic information and reasons for cancellations. Results We analysed records from the participating hospitals, with an overall cancellation rate of 9.7% (508/5231) on the DOS for elective surgical operations. Of these, 74% were avoidable cancellations. A majority (30%) of these 508 cancellations were attributed to insufficient resources, 28% due to patient's refusal or failure to show-up, and 22% due to change in patient's medical status. Conclusion We saw a preponderance of avoidable reasons for elective surgery cancellations. A multidisciplinary approach with adequate preoperative patient counselling, timely communication between the patients and caregivers, adequate preoperative anaesthetic assessment, and planning by the surgical team may help reduce the cancellation rate.

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This study identified factors associated with adherence to a 6-month isoniazid preventive therapy (IPT) course among adolescents and children living with HIV. Forty adolescents living with HIV and 48 primary caregivers of children living with HIV completed a Likert-based survey to measure respondent opinions regarding access to care, quality of care, preferred regimens, perceived stigma, and confidence in self-efficacy. Sociodemographic data were collected and adherence measured as the average of pill counts obtained while on IPT. The rates of suboptimal adherence (< 95% adherent) were 22.5% among adolescents and 37.5% among the children of primary caregivers. Univariate logistic regression was used to model the change in the odds of suboptimal adherence. Independent factors associated with suboptimal adherence among adolescents included age, education level, the cost of coming to clinic, stigma from community members, and two variables relating to self-efficacy. Among primary caregivers, child age, concerns about stigma, and location preference for meeting a community-health worker were associated with suboptimal adherence. To determine whether these combined factors contributed different information to the prediction of suboptimal adherence, a risk score containing these predictors was constructed for each group. The risk score had an AUC of 0.87 (95% CI: 0.76, 0.99) among adolescents and an AUC of 0.76 (95% CI: 0.62, 0.90), among primary caregivers suggesting that these variables may have complementary predictive utility. The heterogeneous scope and associations of these variables in different populations suggests that interventions aiming to increase optimal adherence will need to be tailored to specific populations and multifaceted in nature. Ideally interventions should address both long-established barriers to adherence such as cost of transportation to attend clinic and more nuanced psychosocial barriers such as perceived community stigma and confidence in self-efficacy.

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