Background The 18kDa Translocator Protein (TSPO) has been proposed as a novel anti-inflammatory drug target. XBD173 and etifoxine are TSPO ligands that modulate inflammatory responses in preclinical models. Limited pharmacokinetic data is available publicly for either molecule. Purpose To derive pharmacokinetic data for orally administered etifoxine and XBD173 in humans and determine the binding affinity of etifoxine for TSPO. Experimental Approach We measured plasma concentrations serially after dosing 4 healthy volunteers with XBD173 90mg once a day (OD) for 7 days or etifoxine 50mg three times a day (TDS) for 7 days. We separately performed competition assays between etifoxine and [3H]PK11195 in human brain tissue to determine its TSPO binding affinity. Key Results The average XBD173 Cmax was 129 ng/mL with free fraction was 0.34%, predicting a maximal free concentration of 1.1 nM. For etifoxine, the average plasma Cmax was 32 ng/mL with a free fraction of 0.29%, predicting a maximal free etifoxine concentration of 0.31 nM. The Ki for etifoxine in human brain was 7.8uM (95% CI 4.5-14.6uM) Conclusion Oral XBD173 dosing at 90mg OD will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50mg TDS. Implications Our pharmacokinetic and brain affinity data suggest that physiological effects of oral XBD173 could be mediated by TSPO, but that any physiological effects of oral etifoxine cannot be a consequence of direct interaction with this target.

Background and purpose Dietary fiber has been used to prevent obesity by regulating the intestinal flora and promoting the production of short-chain fatty acids (SCFAs). However, it is insufficient to conclude the decisive role of microbiota and SCFAs by adding oligosaccharides to foods without caloric balance. Experimental approach The effects of oligosaccharides and their regulated microflora on the development of obesity in mice were studied by designing a high-fat diet with equal calories but different contents of oligosaccharides. Simulation of SCFAs produced by intestinal flora to explore the regulatory mechanisms of bacterial flora in hormone and lipid synthesis. Key results Isocaloric diets demonstrated that appropriate rather than excess oligosaccharides prevent obesity by regulating appetite. Such an appetite was inhibited by oligosaccharides but promoted by SCFAs. Furthermore, promoted appetite was tightly related to decreased insulin and increased acyl-CoA binding protein, which was correlated with SCFA-induced fat degradation. Interestingly, drinking butyrate alleviated obesity even with higher calorie intake. Molecular docking demonstrated that conversion of butyrate to butyryl-CoA converted from butyrate, as a structural analog of acetyl-CoA, inhibits the activity of acetyl-CoA carboxylase. Conclusion and implications Together, these findings demonstrate the limitation of fermentable fiber and provide possible obesity therapeutic targets that inhibit bacterial fermentation or increase the ratio of butyrate/acetate.

Aim: To examine the effects of drug use in the last 6 months before contracting coronavirus disease-2019 (COVID-19) on the clinical course of COVID-19. Methods: In this retrospective cohort study, which included 525 patients diagnosed with COVID-19 between March and November 2020 from four different family health centers in Istanbul, the records of the patients were retrospectively analyzed. In addition to demographic information, all medications used by the patients in the last 6 months before the diagnosis of COVID-19 were noted. The effects of demographic data and medications on the three main endpoints of the study, which were hospitalization, intensive care unit (ICU) admission, and mortality, were analyzed by using logistic regression models. Results: Of the 525 COVID-19 patients included in the study, 109 (20.8%) were hospitalized, 18 (3.4%) were treated in ICU, and 11 (2.1%) patients died. While increasing age is associated with hospitalization, ICU admission and mortality; also, the presence of COVID-19 thoracic computed tomography (CT) findings and polypharmacy were associated with an increased hospitalization; living alone and the presence of COVID-19 thoracic CT findings were associated with an increased ICU admission. When adjusted for age and comorbidity, logistic regression models revealed that medications for diabetes mellitus (DM) increased the probability of hospitalization (OR=3.9, 95% CI 1.2-13.0), and calcium channel blockers (CCBs) increased the probability of ICU admission (OR=15.8, 95% CI 2.1-120.2) and mortality (OR=295.1, 95% CI 4.6-18946.6). Conclusion: Previously utilization of DM medications and CCBs may have negative effects on the clinical course of COVID-19.

Disentangling contributions from environmental variables is crucial for explaining global biodiversity patterns. We use wavelet power spectra to separate wavelength-dependent trends across Earth’s surface. Spectra reveal scale- and location-dependent coherence between species richness and topography (E), annual precipitation (Pn), temperature (Tm) and temperature range (ΔT). >97% of richness of carnivorans, bats, songbirds, hummingbirds and amphibians resides at wavelengths >~103 km. 30-69% is generated at scales >~104 km. At these scales, richness across the Americas is anti-correlated with E and ΔT, and positively correlated with Pn and Tm. Carnivoran richness is incoherent with ΔT, suggesting insensitivity to temperature seasonality. Conversely, amphibian richness is anti-correlated with ΔT at large scales. At scales <~103 km, richness is highest within the tropics. Terrestrial plateaux exhibit coherence between carnivoran richness and E at scales ~103 km, reflecting contributions of orogeny/epeirogeny to biodiversity. Similar findings result from transects across other continents. Scale-dependent sensitivities of vertebrate populations to climate are revealed.

Background: We believe there is a profile of patient with eosinophilic oesophagitis and atopic background, marked by the existence of IgE-mediated sensitizations to environmental and food allergens. We suspect that the prevalence of sensitization to panallergens will be high and this will probably be relevant in terms of the onset and clinical course of the disease. Our aim is to report the observed sensitivities to environmental and food allergens in patients with eosinophilic oesophagitis with atopic background as well as characterizing other markers or analytical parameters in these patients. Methods: We collated clinical and analytical data from 160 adult patients with a reported diagnosis of eosinophilic oesophagitis. These patients were studied between 1 January 2012 and 31 December 2020. During an initial visit skin tests were performed with full batteries of routine aero-allergens and foodstuffs. Patients were subsequently referred for blood test and determination of CAP, blood count and total IgE (in all cases), as well as eosinophilic cation protein and IMMUNOISAC in the centres in which this was available. Results: We were able to detect a broad spectrum of sensitizations to environmental, foodstuffs and panallergens. The most common allergic disease was rhinoconjuntivitis. The sensitizations observed to foodstuffs were atypical for the adult population and were not responsible for manifestations compatible with immediate allergy. An important percentage of patients presented seasonal worsening of choking symptoms. Conclusions: We should be able to identify patients with eosinophilic oesophagitis and atopic background. Identifying this phenomenon would enable giving dietary and environmental recommendations as well as more specific and effective treatments to our patients.

A document by Marek Mikolajczyk. Click on the document to view its contents.

An implicit compact scheme is proposed to approximate the solution of parabolic partial differential equations (PDEs) of Burger’s type in two-dimensions. These nonlinear PDEs are essential because of the description of various mechanisms in engineering and physics. The nonlinear convective and advection are discretized with high-order accuracy on an arbitrary grid, which results in a family of high-resolution discrete replacements of given PDEs. The essence of the new scheme lies in its compact character and two-level single-cell discretization so that one discrete equation leads to the accuracy of orders three or four depending upon the choice of the grid network. The consistency and stability preserving third-order spatial accuracy and second-order accurate time discretization are described by Fourier analysis applied to the linearized error equations. The scheme is used for solving celebrated nonlinear PDEs, such as the non-degenerate convection-diffusion equation, generalized Burgers-Huxley equation, Buckley-Leverett equation, and Burgers-Fisher equation. Many computational results are presented to demonstrate the high-resolution character of the newly proposed scheme.

This study analyzes the similarity factor f2 within in vitro drug release profiles of modified-release (MR) dosage form. The Cubic Spline Interpolation (CSI) method is used to estimate the percentage drug release at intermediate time points; to reduce the difference between MR drug release profiles in the ex vivo environment. In this study, the cubic spline interpolation approach assesses the similarity factor f2 and a pair-wise comparative analysis between two different formulations of Quetiapine Fumarate MR tablets and one formulation of Venlafaxine HCl MR tablets. This analysis explains the interpretation and comparison of supplemental mediating timepoint observations. This method may aid industries in monitoring the characteristics of in vitro release studies with a few changes in timepoint selection and intensifying similarity factor f2 for early-stage drug dosage form preparation.

Viral infections and seasonality are linked with trends in new pediatric leukemia and lymphoma cases. The COVID-19 pandemic disrupted this norm, and subsequently the international medical community observed a decrease in new diagnoses of hematologic cancers in children. However, this was not the trend observed at Cohen Children's Medical Center where, despite examining fifteen months during the COVID-19 pandemic, we did not see a statistically significant decrease in monthly cases. Rather, cases remained constant as compared to pre-COVID-19 periods. This warrants further study at a multi-institutional level to investigate the association between COVID-19 and rates of pediatric leukemia and lymphoma.

Hereditary spherocytosis (HS) and hereditary distal renal tubular acidosis (dRTA) could share a common pathogenesis, related to defects in band 3 anion exchanger 1 (AE1), encoded by the human solute carrier family 4 anion exchanger member 1 (SLC4A1) gene. SLC4A1 is expressed both in the red blood cell membrane (eAE1) and in distal tubules of the kidney (kAE1), its mutations may result in red blood cells dysmorphology and impaired urinary acidification. We describe a 7 years-old Italian boy with coexisting HS and dRTA caused by a novel SLC4A1 mutation, confirming that HS and dRTA could be part of a multisystemic disease requiring multidisciplinary approach.

Nelarabine, a prodrug of arabinosylguanine has lineage-specific toxicity for T lymphoblasts and is used to treat refractory or relapsed T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma patients. The most commonly observed adverse effects associated with nelarabine are mainly haematological i.e., neutropenia, anaemia, and thrombocytopenia. Additionally, neurological, and gastrointestinal toxicities have been reported. Neurotoxicity associated with nelarabine is rare. Here, we presented a young adult patient diagnosed with T-ALL who experienced a nucleus caudatus infarction, and toxic leukoencephalopathy (TL) during treatment with nelarabine. Computed tomography and magnetic resonance imaging have shown periventricular and nucleus caudatus abnormalities. Radiological findings suggested TL and acute infarct of right nucleus caudatus. After high-dose steroids, intravenous immunoglobulin, and support treatment, his neurologic symptoms disappeared except for mild peroral numbness. However, radiological sequelae persisted despite clinical improvement. Physicians involved in the care of these patients who use nelarabine should be aware of the fact that cerebral toxicity of the nelarabine may occur especially in the presence of predisposing factors. It is crucial to monitor closely those patients receiving nelarabine and also those who have additional predisposing factors for neurotoxicity.

Background: To report our experience with image guided pencil beam proton beam therapy (PBT) for craniospinal irradiation (CSI). Materials and Methods: Between January 2019 to Dec 2021, we carried out a detailed audit of the first forty patients treated with PBT. We had recorded acute toxicities, reporting early outcomes and discuss limitations of current contouring guidelines during CSI PBT planning. Results: Median age of the patient cohort was 8 years, and histologies include 20 medulloblastoma, 7 recurrent ependymoma, 3 pineoblastoma, 3 were germ cell tumors and remaining 7 constituted other diagnoses. Forty percent patients received concurrent chemotherapy. Median CSI dose was 23.4 GyE (Gray Equivalent; range 21.6 - 35). Thirty-five patients (87.5%) completed their CSI without interruption, 5 required hospital admission. No patient had grade 2/> weight loss during the treatment. Forty-five percent (18) developed grade 1 haematological toxicities and 20% (8) developed grade 2 or 3 toxicities; none had grade 4 toxicities. At median follow up of 12 months, 90 % patients are alive of whom 88.9 % are having local control. Special consideration with modification in standard contouring used at our institute helped in limiting acute toxicities in paediatric CSI patients. Conclusion: Our preliminary experience with modern contemporary PBT using pencil beam technology and daily image guidance in a range of tumours suitable for CSI is encouraging. Patients tolerated the treatment well with acceptable acute toxicity and expected short-term survival outcome. In paediatric CSI patients, modification in standard contouring guidelines required to achieve better results with PBT.

This study aimed to establish a predictive model of severe adenovirus pneumonia in children based on low-dose CT imaging and clinical features of the chest and evaluate the model.This retrospective study included 177 pediatric adenovirus patients who underwent low-dose CT scans between January 2019 and August 2019. We collected clinical and imaging manifestations, complications, and laboratory test indicators in two groups of children and conducted all statistical analyses. Using a logistic regression model to analyze severe adenovirus pneumonia risk factors in children. We constructed a prediction model by drawing a nomogram and verified the predictive efficacy of the model through the ROC curve.The difference was statistically significant （P<0.05） between the mild adenovirus pneumonia group and the severe adenovirus pneumonia group in gender, age, weight, body temperature, L/N ratio, LDH, ALT, AST, CK-MB, adenovirus DNA loads, bronchial inflation sign, emphysema, ground glass sign, bronchial wall thickening, bronchiectasis, pleural effusion, consolidation score, and lobular inflammation score. Multivariate logistic regression analysis showed that gender, LDH value, emphysema, consolidation score, and lobular inflammation score were severe independent risk factors for adenovirus pneumonia in children. Logistic regression was employed to construct clinical models, imaging semantic feature models, and combined models. The clinical decision curve analysis demonstrates the clinical application value of the nomogram prediction model.The comprehensive nomogram prediction model, based on low-dose chest CT imaging and clinical data, can predict the high-risk factors of severe adenovirus pneumonia in children and has good clinical application value.

The current outbreak of COVID-19, caused by SARS-CoV-2, has resulted in millions of deaths and hospitalizations worldwide, as well as an extreme impact in our social-economic lives. The emergency to implement public health measures, such as, social distancing, high levels of testing and vaccination has shown the importance of continuous research in those areas. Here it will be presented the most relevant knowledge on the SARS-CoV-2 genomic features and mechanism that lies beneath its ability to surpass the immunological system. Moreover, it will be discussed the virus new variants and the potential impact that they can have on pathogenic factors and on the detection methods effectiveness. In order to better manage the pandemic, it is essential to maintain continuous research into the SARS-CoV-2 genome and a strict real-time genomic surveillance at the global level. This will allow the scientific community to understand the evolution of the virus and track the emergence of new mutations, which may affect the performance of COVID-19 tests. In this sense, the technologies developed for SARS-CoV-2 detection and their advantages and limitations will be fully explored.

Background: An important pathogenic mechanism in the development of pulmonary arterial hypertension (PAH) is hypothesized to be the pulmonary vascular remodeling, in which cancer-like pulmonary arterial smooth muscle cells (PASMCs) proliferation and perivascular inflammation play an important role. Ginsenoside compound K (G-CK) exhibits anticancer and anti-inflammation properties. However, whether or not G-CK could protect against PAH in rats is still unknown. Objective: The aim was to investigate whether or not G-CK attenuates PAH, if so, to elucidate the molecular mechanisms underlying its effects. Methods and Results: we established PAH rat models by left pneumonectomy combined with monocrotaline, and PAH rats were treated G-CK in the prevention (on 7 th day) and reversal group (on 21th day) respectively. The weekly body weight, the survival rate, mean pulmonary arterial pressure and right ventricle hypertrophy index of prevention group and reversal group improved to varying degrees. Hematoxylin and eosin and elastic Van Gieson staining of lung tissue showed that the increased of wall thickness, vescular occlusion score and the degree of neointimal proliferation in the model group were mitigated by G-CK. Immunohistochemical analysis of Ki67 and α-smooth muscle actin showed that G-CK suppressed proliferation of PASMCs and muscularization compared with model group. Moreover, G-CK inhibited NF-κB/Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signalling and reduced IL-18, TNF‐α, IL‐6, and IL‐1β in lung tissue by western blot.

Human impacts are the major threat to health and well-being of forest animals. Primates are particularly vulnerable to various anthropogenic disturbances; therefore, in all taxa, they are threatened by various human factors. This review summarizes anthropogenic factors such as forest fragmentation, degradation, logging, direct human interactions, and primate responses by reviewing the results presented in various research papers. Humans are changing landscapes around the world through overexploitation and consumption of natural resources. Behavior changes in food composition and diversity, population density, group size, and the adult gender relationship in groups are some examples. Habitat fragmentation is a landscape-scale process in which continuous habitat is broken down into small pieces scattered in a non-habitat matrix, which can lead to the loss of many primate species. In general, human invasion can result in habitat loss and fragmentation into various fragments. In addition, primate fragment-scale responses can vary significantly in landscapes of different habitats and composition. Study on primate diversity in the African continent shows that primate species have shown a classical species-area relationship, and of primate species that may become extinct in the country due to deforestation. In this review, I provide clear and consistent terminology to help future studies precisely address the effects of anthropogenic disturbance on primates and to help to form a body of literature where comparisons among studies are possible.

Previous cultural evolutionary analyses have used neutral models as null models to distinguish between the unbiased copying and the biased transmission of cultural traits. Here, we define economic and ecological concepts as cultural traits that constitute a complex system representing sustainability ideas. We analyse the frequency distribution, turnover and innovation rates of 3,713 concepts appearing in China’s mainstream newspaper, People’s Daily, from 1946 to 2015. Results reveal that (1) economic concepts show a stronger tendency towards random copying than ecological concepts; (2) popular economic ideas experience anti-conformist bias, while ecological ideas experience conformist bias; (3) the differences in popular concept variability indicate that cultural drifts are stronger in disciplinary domains than in cross-disciplinary domains; and (4) the frequency change in popular sustainability ideas also suggests positive selection due to political strategy and governmental behaviour. The study can promote vibrant and resilient ecological knowledge to foster sustainability activities and behaviours.

Background: Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice outcomes are available. Objectives: To evaluate the effect of 16 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice. Method: Patients visited the outpatient clinic at baseline, and after 4 and 16 weeks of treatment. Endpoints were proportions of patients achieving ≥50%, ≥75% or ≥90% improvement in Eczema Area and Severity Index (EASI), (almost) clear on Investigator Global Assessment (IGA) and ≥4 points reduction in Patient-Oriented Eczema Measure (POEM), Numeric Rating Scale (NRS)-pruritus, and -pain score at 16 weeks. Patients achieving absolute cutoff scores indicating controlled disease (EASI ≤7, POEM ≤7, NRS-pruritus ≤4) were analyzed. Nineteen severity-associated serum biomarkers were measured using Luminex-based multiplex immunoassays, and predicted-EASI (p-EASI) was calculated. Results: Forty-seven patients were included. Respectively 76.6%, 40.4%, and 19.1% reached EASI-50, EASI-75 and EASI-90, and 25.5% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain score was reached by 65.2%, 50.0%, and 79.2%, respectively. After 16 weeks, 83.0% achieved ≥1 cutoff score indicating controlled disease. Most frequently reported side effects were conjunctivitis (n=3 (6.4%)), hair loss (n=3) and headache (n=3). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significantly high correlation with disease severity. Conclusion: Dupilumab treatment significantly improved disease severity and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice.

Probiotics have been used as one of the most promising dietary interventions to alleviate disease transmission in aquaculture. However, there are limited studies on probiotic uses in modulating the highly contagious virus such as tilapia lake virus (TiLV) that is seriously threatening global tilapia production. We assessed commercially available probiotic supplement use in TiLV-infected tilapia and performed mortality and cohabitation assays. We developed a mechanistic approach to predict dose-response interactions of probiotic effects on mortality and innate immune gene response. We used a susceptible-infected-mortality disease model to assess key epidemiological parameters known as transmission rate and basic reproduction number ( R 0) based on our viral load dynamics data. We found that the most marked benefits of probiotics are significantly associated with immune system enhancements (~30%) and disease transmission (~80%) and R 0 (~70%) reductions in tilapia populations, resulting in a higher tolerance of farming densities (~400 folds) in aquaculture. These findings provide early insights as to how probiotic use-related factors may influence TiLV transmission and the immune responses in TiLV-infected tilapia. Our study facilitates understanding the mode of action of probiotics in disease containment and predicting better probiotic dosages in diet and supplements to achieve the optimal culturing conditions. Overall, our analysis assures that further study of rationally designed and targeted probiotics, or mechanistic modeling is warranted on the basis of promising early data of this approach.

Objectives: Over the last two decades, mean number of otolaryngology applications-per-candidate has increased by 250%. Otolaryngology-specific requirements were piloted to minimize applicant and program burdens. We investigated the impact of introducing and then removing these pre-match requirements on Match outcomes. Methods: 2014–2021 National Resident Matching Program® (NRMP) data was examined. Primary outcome was impact of otolaryngology resident talent assessment (ORTA; conducted pre-match 2017, post-match 2019) and program specific paragraph (PSP; implemented 2016, made optional 2018) on applicant numbers and match rates. Secondary analysis of a survey distributed to post-graduate year one and two (PGY-1/PGY-2) otolaryngology residents assessed candidate perceptions. Results: Applicant numbers declined significantly during PSP/ORTA (18.9%,P=0.001). After changes to optional PSP and post-match ORTA, applicant numbers increased significantly (39.0%,P=0.002). Examined individually, mandatory PSP was associated with a significant decline in applicants (P=0.007), whereas post-match ORTA was associated with significant increases in applicants (P=0.010). ORTA and PSP negatively impacted the decision to apply into otolaryngology in 59.8% and 51.3% of applicants, respectively. Conversely, match rate success improved significantly from 74.8% to 91.2% during PSP/ORTA (P=0.014), followed by significant decline to 73.1% after PSP was made optional and ORTA moved to post-match (P=0.002). Conclusion: Both the ORTA and PSP were associated with declines in applicant numbers and increases in match rate success. The ORTA move to post-match demonstrated the most impact on increasing candidate numbers. As programs seek ways to remove barriers to applying into otolaryngology, the potential consequences of an increasing pool of unmatched candidates must also be considered.

Environmental and anthropogenic stressors interact to determine the composition and performance of biological systems. Given the interactive nature of multiple stressors and the plethora of metrics used for measuring ecosystem value, we advocate for discussion around efforts that integrate multiple stressor research with ecosystem multifunctionality. This new perspective will contribute to a better understanding of the emergent threats of global change on ecosystem functioning and provide valuable information concerning conservation practices and measures.

Objectives: This systematic review summarizes all published uterine hemangioma cases in pregnant women. Search strategy: The databases PubMed and Scopus were searched systematically. The reference lists of all retrieved articles were also screened. Selection criteria: The online tool Rayyan QCRI was used for registration of the selection process. Articles reporting on cases of uterine hemangioma in pregnancy were included, non-English articles were excluded. Data collection and analysis: Data extraction was done by one reviewer and thereafter verified by the second reviewer. All data were described in a narrative format. Results: Fifteen case reports were included. In most cases, the diagnosis was established by antenatal ultrasound and pregnancy course was uneventful. More than half of the patients developed a postpartum hemorrhage, necessitating a hysterectomy for bleeding control in four cases, although the risk for both seemed lower in those patients in whom the hemangioma was diagnosed before delivery. One case of maternal mortality and two cases of fetal death were reported. There was one case of neonatal respiratory morbidity, although the neonatal data were not routinely reported upon. Conclusion: Current knowledge on uterine hemangioma in pregnancy is limited, but it seems to hold substantial risks for both mother and child. We recommend routine screening for this condition at the standard mid-trimester anomaly scan. Pregnant women with uterine hemangioma should ideally be cared for in centers of expertise. An international registry will help to build a better understanding of this rare pathology. Funding: None.

Background. Urine is a common matrix for screening for cannabis use. Urine assays typically measure total THCCOOH concentrations after hydrolysis cleaves the glucuronide. Urine THCCOOH concentration is adjusted by urine creatinine concentration or specific gravity, to account for variable hydration states. Therefore, we performed a population pharmacokinetic analysis of the urinary THCCOOH excretion, urinary flow rate, and creatinine excretion rate data. Methods. Urine was obtained over 168 hours from 6 subjects who smoked low (15.8 mg) and high dose (33.8 mg) THC cigarettes on two occasions. Samples were analyzed for THCCOOH concentration by GC/MS and volume, time and creatinine concentration measured. A population pharmacokinetic model of the urinary clearance of THCCOOH was created from these data and potential covariates of urine creatinine concentration and urine creatinine excretion rate were assessed. Results. Elimination clearance of THCCOOH was estimated as 0.104 ± 0.088 L/min and its urinary clearance was 0.0022 ± 0.0015 L/min. Total urine excretion of THCCOOH was estimated a 2.3%. Urine flow rate and urine creatinine concentrations were significantly correlated, r2 0.35. Creatinine excretion rate was 129.6 ± 71.0 mL/min and the intra-subject variability was 31-52% (SD%) during the week. Urinary creatinine excretion rate was a significant covariate for the urinary clearance of THCCOOH. Conclusions. Creatinine Clearance is a significant covariate for urinary THCCOOH clearance. Only 2-3% of bioavailable THC is excreted as THCCOOH and THCCOO-glucuronide via the urine. Correction of urine drug and/or metabolite concentration with urine creatinine concentration or specific gravity may be more problematic than previously appreciated.

Hypoxia Inducible Factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism and glucose metabolism. This protein regulates the expressions of Lactate Dehydrogenase (LDH) and Pyruvate Dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into Acetyl Coenzyme A which leads to reduced usage of the Tricarboxylic Acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumour growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzymes regulation pathways were solved for each cell of the tumour represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumour development caused by cell consumption and reduced diffusion inside the tumour. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. The results also show that targeting the upregulation of LDH and the downregulation of PDH could be relevant in therapy.