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Hydrazoic acid (HN3) is used as a case study for investigating the accuracy and precision by which a molecular structure—specifically, a semi-experimental equilibrium structure (reSE)—may be determined using current state-of-the-art methodology. The influence of the theoretical corrections for effects of vibration–rotation coupling and electron-mass distribution that are employed in the analysis is explored in detail. The small size of HN3 allowed us to deploy considerable computational resources to probe the basis-set dependence of these corrections using a series of coupled-cluster single, double, perturbative triple [CCSD(T)] calculations with cc-pCVXZ (X = D, T, Q, 5) basis sets. We extrapolated the resulting corrections to the complete basis set (CBS) limit to obtain CCSD(T)/CBS corrections, which were used in a subsequent reSE structure determination. The reSE parameters obtained using the CCSD(T)/cc-pCV5Z corrections are nearly identical to those obtained using the CCSD(T)/CBS corrections, with uncertainties in the bond distances and angles of less than 0.0006 Å and 0.08°, respectively. The previously obtained reSE structure using CCSD(T)/ANO2 agrees with that using CCSD(T)/cc-pCV5Z to within 0.000 08 Å and 0.016° for bond distances and angles, respectively, and with only 25% larger uncertainties, validating the idea that reSE structure determinations can be carried out with significantly smaller basis sets than those needed for similarly accurate, strictly ab initio determinations. Although the purely computational re structural parameters [CCSD(T)/cc-pCV6Z] fall outside of the statistical uncertainties (2σ) of the corresponding reSE structural parameters, the discrepancy is rectified by applying corrections to address the theoretical limitations of the CCSD(T)/cc-pCV6Z geometry with respect to basis set, electron correlation, relativity, and the Born–Oppenheimer approximation, thereby supporting the contention that the semi-experimental approach is both an accurate and vastly more efficient method for structure determinations than is brute-force computation. [ABSTRACT FROM AUTHOR]

Hydrazoic acid (HN3) is used as a case study for investigating the accuracy and precision by which a molecular structure—specifically, a semi-experimental equilibrium structure (reSE)—may be determined using current state-of-the-art methodology. The influence of the theoretical corrections for effects of vibration–rotation coupling and electron-mass distribution that are employed in the analysis is explored in detail. The small size of HN3 allowed us to deploy considerable computational resources to probe the basis-set dependence of these corrections using a series of coupled-cluster single, double, perturbative triple [CCSD(T)] calculations with cc-pCVXZ (X = D, T, Q, 5) basis sets. We extrapolated the resulting corrections to the complete basis set (CBS) limit to obtain CCSD(T)/CBS corrections, which were used in a subsequent reSE structure determination. The reSE parameters obtained using the CCSD(T)/cc-pCV5Z corrections are nearly identical to those obtained using the CCSD(T)/CBS corrections, with uncertainties in the bond distances and angles of less than 0.0006 Å and 0.08°, respectively. The previously obtained reSE structure using CCSD(T)/ANO2 agrees with that using CCSD(T)/cc-pCV5Z to within 0.000 08 Å and 0.016° for bond distances and angles, respectively, and with only 25% larger uncertainties, validating the idea that reSE structure determinations can be carried out with significantly smaller basis sets than those needed for similarly accurate, strictly ab initio determinations. Although the purely computational re structural parameters [CCSD(T)/cc-pCV6Z] fall outside of the statistical uncertainties (2σ) of the corresponding reSE structural parameters, the discrepancy is rectified by applying corrections to address the theoretical limitations of the CCSD(T)/cc-pCV6Z geometry with respect to basis set, electron correlation, relativity, and the Born–Oppenheimer approximation, thereby supporting the contention that the semi-experimental approach is both an accurate and vastly more efficient method for structure determinations than is brute-force computation. [ABSTRACT FROM AUTHOR]

Nitazoxanide use is limited by gastrointestinal side effects associated with increasing dose. In this drug repurposing study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. In this crossover drug–drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alone and in combination with 300/100 mg atazanavir/ritonavir in period 1 and 2 respectively. On both days, blood samples for intensive pharmacokinetic analyses were collected at 0–12 h post-dose. To explore the utility of dried blood spots (DBS) as an alternative to plasma for tizoxanide quantification, 50 µL of blood from some participants was spotted on DBS cards and correlated with plasma concentrations. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between both periods. Co-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure [GMR (90% CI) of AUC0–12h, Cmax and C12h being 1.872 (1.870–1.875), 2.029 (1.99–2.07) and 3.14 (2.268–4.352), respectively]. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma concentrations, and there was strong correlation (R = 0.95, p < 0.001) between DBS-derived plasma concentration and plasma concentrations. Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers. [ABSTRACT FROM AUTHOR]

Circulating, soluble polymer–drug conjugates have been utilised for many years to aid the delivery of sensitive, poorly-soluble or cytotoxic drugs, prolong circulation times or minimise side effects. Long-acting therapeutics are increasing in their healthcare importance, with intramuscular and subcutaneous administration of liquid formulations being most common. Degradable implants also offer opportunities and the use of polymer–prodrug conjugates as implant materials has not been widely reported in this context. Here, the potential for polymer–prodrug conjugates of the water soluble nucleoside reverse transciption inhibitor emtricitabine (FTC) is studied. A novel diol monomer scaffold, allowing variation of prodrug substitution, has been used to form polyesters and polycarbonates by step-growth polymerisation. Materials have been screened for physical properties that enable implant formation, studied for drug release to provide mechanistic insights, and tunable prolonged release of FTC has been demonstrated over a period of at least two weeks under relevant physiological conditions. [ABSTRACT FROM AUTHOR]

Background: In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended screening for prediabetes and diabetes among adults aged 35–70 years with overweight or obesity. Studying dysglycemia screening in federally qualified health centers (FQHCs) that serve vulnerable patient populations is needed to understand health equity implications of this recommendation. Objective: To investigate screening practices among FQHC patients who would be eligible according to the 2021 USPSTF recommendation. Design: Retrospective cohort study analyzing electronic health records from a national network of 282 FQHC sites. Participants: We included 183,329 patients without prior evidence of prediabetes or diabetes, who had ≥ 1 office visit from 2018–2020. Main Measures: Screening eligibility was based on age and measured body mass index (BMI). The primary outcome, screening completion, was ascertained using hemoglobin A1c or fasting plasma glucose results from 2018–2020. Key Results: Among 89,543 patients who would be eligible according to the 2021 USPSTF recommendation, 53,263 (59.5%) were screened. Those who completed screening had higher BMI values than patients who did not (33.0 ± 6.7 kg/m2 vs. 31.9 ± 6.2 kg/m2, p < 0.001). Adults aged 50–64 years had greater odds of screening completion relative to younger patients (OR 1.13, 95% CI: 1.10–1.17). Patients from racial and ethnic minority groups, as well as those without health insurance, were more likely to complete screening than White patients and insured patients, respectively. Clinical risk factors for diabetes were also associated with dysglycemia screening. Among patients who completed screening, 23,588 (44.3%) had values consistent with prediabetes or diabetes. Conclusions: Over half of FQHC patients who would be eligible according to the 2021 USPSTF recommendation were screened. Screening completion was higher among middle-aged patients, those with greater BMI values, as well as vulnerable groups with a high risk of developing diabetes. Future research should examine adoption of the 2021 USPSTF screening recommendation and its impact on health equity. [ABSTRACT FROM AUTHOR]

Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC90) (0.664 µg/mL) and >8 × PA-IC90 (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC90. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP. [ABSTRACT FROM AUTHOR]

The article presents the discussion on meant the gods of the Olympian pantheon, and a battlefield of heroes. Topics include Sordello's poetical ambitions and his view of the world as immaterial are collapsed together by the phrase "that aëry magnificence"; and skepticism draws into scrutiny not only the possibility of ontology, but also, as a side effect, the possibility of epic.