High-throughput approaches to uncover synergistic drug combinations in leukemia.

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Electronic pillbox-enabled self-administered therapy versus standard directly observed therapy for tuberculosis medication adherence and treatment outcomes in Ethiopia (SELFTB): protocol for a multicenter randomized controlled trial.

BACKGROUND: To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives. METHODS: This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers. DISCUSSION: This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Coulomb explosion imaging of CH3I and CH2ClI photodissociation dynamics.

The photodissociation dynamics of CH3I and CH2ClI at 272 nm were investigated by time-resolved Coulomb explosion imaging, with an intense non-resonant 815 nm probe pulse. Fragment ion momenta over a wide m/z range were recorded simultaneously by coupling a velocity map imaging spectrometer with a pixel imaging mass spectrometry camera. For both molecules, delay-dependent pump-probe features were assigned to ultraviolet-induced carbon-iodine bond cleavage followed by Coulomb explosion. Multi-mass imaging also allowed the sequential cleavage of both carbon-halogen bonds in CH2ClI to be investigated. Furthermore, delay-dependent relative fragment momenta of a pair of ions were directly determined using recoil-frame covariance analysis. These results are complementary to conventional velocity map imaging experiments and demonstrate the application of time-resolved Coulomb explosion imaging to photoinduced real-time molecular motion.

Acute elevation of lipids does not alter exercise hemodynamics in healthy men: A randomized controlled study.

OBJECTIVE: Exaggerated exercise blood pressure (BP) predicts mortality. Some studies suggest this could be explained by chronic hyperlipidemia, but whether acute-hyperlipidemia effects exercise BP has never been tested, and was the aim of this study. METHODS: Intravenous infusion of saline (control) and Intralipid were administered over 60 min in 15 healthy men by double-blind, randomized, cross-over design. Brachial and central BP (including, pulse pressure, augmentation pressure and augmentation index), cardiac output and systemic vascular resistance were recorded at rest and during exercise. RESULTS: Compared with control, Intralipid caused significant increases in serum triglycerides, very low density lipoproteins and free fatty acids (p < 0.001 for all). However, there was no significant difference for any exercise hemodynamic variable (p > 0.05 for all). CONCLUSION: Acute-hyperlipidemia does not significantly change exercise hemodynamics in healthy males. Therefore, the association between raised lipids and increased exercise BP is likely due to the chronic effects of hyperlipidemia.

Strategies for treating latent multiple-drug resistant tuberculosis: a decision analysis.

BACKGROUND: The optimal treatment for latent multiple-drug resistant tuberculosis infection remains unclear. In anticipation of future clinical trials, we modeled the expected performance of six potential regimens for treatment of latent multiple-drug resistant tuberculosis. METHODS: A computerized Markov model to analyze the total cost of treatment for six different regimens: Pyrazinamide/ethambutol, moxifloxacin monotherapy, moxifloxacin/pyrazinamide, moxifloxacin/ethambutol, moxifloxacin/ethionamide, and moxifloxacin/PA-824. Efficacy estimates were extrapolated from mouse models and examined over a wide range of assumptions. RESULTS: In the base-case, moxifloxacin monotherapy was the lowest cost strategy, but moxifloxacin/ethambutol was cost-effective at an incremental cost-effectiveness ratio of $21,252 per quality-adjusted life-year. Both pyrazinamide-containing regimens were dominated due to their toxicity. A hypothetical regimen of low toxicity and even modest efficacy was cost-effective compared to "no treatment." CONCLUSION: In our model, moxifloxacin/ethambutol was the preferred treatment strategy under a wide range of assumptions; pyrazinamide-containing regimens fared poorly because of high rates of toxicity. Although more data are needed on efficacy of treatments for latent MDR-TB infection, data on toxicity and treatment discontinuation, which are easier to obtain, could have a substantial impact on public health practice.

An investigation of satellite hemodialysis fallbacks in the province of Ontario.

BACKGROUND AND OBJECTIVES: In Ontario, Canada, hemodialysis services are organized in a "hub and spoke" model comprised of regional centers (hubs), satellites, and independent health facilities (IHFs; spokes). Rarely is a nephrologist on site when dialysis treatments take place at satellite units or IHFs. Situations occur that require transfer of the patient back ("fallbacks") to the regional center that necessitate either in- or outpatient care. Growth in the satellite dialysis population has led to an increased burden on the regional centers. This study was carried out to determine the incidence, nature, and outcome of such fallbacks to aid resource planning. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were collected on 565 patients from five regional centers over 1 yr. These regional centers controlled 19 satellite dialysis centers including 7 IHFs. RESULTS: There were 681 fallbacks in 328 patients: 1.21 incidents per patient or 2.1 incidents per patient year. Multiple fallbacks occurred in 170 patients. Fallback episodes lasted a mean of 10.3 d, requiring 4.6 dialysis treatments. Forty-five percent of fallbacks required hospitalization with a mean stay of 16.7 d. Access-related problems (33%) and nondialysis medical causes (32%) were the major causes of fallback. Resolution of the problem occurred in 87.8%, with the patient returning to the satellite. By the end of the study 77.3% were still satellite patients, 10.8% died, 3.8% returned to the regional center, 3.4% were transplanted, and 4.7% were transferred to other treatment modalities. CONCLUSIONS: Fallbacks are common, yet the model operates well.