Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements

Two Massive Jupiters in Eccentric Orbits from the TESS Full-frame Images

We report the discovery of two short-period massive giant planets from NASA's Transiting Exoplanet Survey Satellite (TESS). Both systems, TOI-558 (TIC 207110080) and TOI-559 (TIC 209459275), were identified from the 30 minute cadence full-frame images and confirmed using ground-based photometric and spectroscopic followup observations from TESS's follow-up observing program working group. We find that TOI-558 b, which transits an F-dwarf (M-* =1.349(-0.065)(+0.064) M-circle dot, R-* =1.496(-0.040)(+0.042) R-circle dot, T-eff = 6466(-93)(+95) K, age 1.79(-0.73)(+0.91) Gyr) with an orbital period of 14.574 days, has a mass of 3.61 +/- 0.15 M-J, a radius of 1.086(-0.038)(+0.041) R-J, and an eccentric (e = 0.300(-0.020)(+0.022)) orbit. TOI-559 b transits a G dwarf (M-* = 1.026 +/- 0.057 M-circle dot, R-* =1.233(-0.026)(+0.028) R-circle dot, T-eff = 5925(-76)(+85) K, age 6.8(-2.0)(+2.5) Gyr) in an eccentric (e = 0.151 +/- 0.011) 6.984 days orbit with a mass of 6.01(-0.23)(+0.24) M-J and a radius of 1.091(-0.025+)(0.028) R-J. Our spectroscopic follow up also reveals a long-term radial velocity trend for TOI-559, indicating a long-period companion. The statistically significant orbital eccentricity measured for each system suggests that these planets migrated to their current location through dynamical interactions. Interestingly, both planets are also massive (>3 M-J), adding to the population of massive giant planets identified by TESS. Prompted by these new detections of high-mass planets, we analyzed the known mass distribution of hot and warm Jupiters but find no significant evidence for multiple populations. TESS should provide a near magnitude-limited sample of transiting hot Jupiters, allowing for future detailed population studies

Reducing catheter-associated urinary tract infections: a systematic review of barriers and facilitators and strategic behavioural analysis of interventions

BACKGROUND: Reducing the need for antibiotics is crucial in addressing the global threat of antimicrobial resistance. Catheter-associated urinary tract infection (CAUTI) is one of the most frequent device-related infections that may be amenable to prevention. Interventions implemented nationally in England target behaviours related to catheter insertion, maintenance and removal, but the extent to which they target barriers to and facilitators of these behaviours is unclear. This strategic behavioural analysis applied behavioural science frameworks to (i) identify barriers to and facilitators of behaviours that lead to CAUTI (CAUTI-related behaviours) in primary, community and secondary care and nursing homes; (ii) describe the content of nationally adopted interventions; and (iii) assess the extent to which intervention content is theoretically congruent with barriers and facilitators. METHODS: A mixed-methods, three-phased study: (1) systematic review of 25 studies to identify (i) behaviours relevant to CAUTI and (ii) barriers to and facilitators of CAUTI-related behaviours, classified using the COM-B model and Theoretical Domains Framework (TDF); (2) content analysis of nationally adopted CAUTI interventions in England identified through stakeholder consultation, classified using the Behaviour Change Wheel (BCW) and Behaviour Change Techniques Taxonomy (BCTTv1); and (3) findings from 1 and 2 were linked using matrices linking COM-B and TDF to BCW/BCTTv1 in order to signpost to intervention design and refinement. RESULTS: The most frequently reported barriers to and facilitators of CAUTI-related behaviours related to 'environmental context and resources'; 'knowledge'; 'beliefs about consequences'; 'social influences'; 'memory, attention and decision processes'; and 'social professional role and identity.' Eleven interventions aiming to reduce CAUTI were identifed. Interventions were primarily guidelines and included on average 2.3 intervention functions (1-5) and six BCTs (2-11), most frequently 'education', 'training' and 'enablement.' The most frequently used BCT was 'information about health consequences' which was used in almost all interventions. Social professional role and identity and environmental context and resources were targeted least frequently with potentially relevant BCTs. CONCLUSIONS: Interventions incorporated half the potentially relevant content to target identifed barriers to and facilitators of CAUTI-related behaviours. There were missed opportunities for intervention as most focus on shaping knowledge rather than addressing motivational, social and environmental influences. This study suggests that targeting motivational, social and environmental influences may lead to more effective intervention design and refinement