Association between healthy behaviors and healthcare resource use with subsequent positive airway pressure therapy adherence in obstructive sleep apnoea.

BACKGROUND: The healthy adherer effect (HAE) has gained increasing attention as potential source of bias in observational studies examining the association of positive airway pressure (PAP) adherence with health outcomes in obstructive sleep apnea (OSA). RESEARCH QUESTION: Is adherence to PAP associated with healthy behaviors and healthcare resource use prior to device prescription? METHODS: Data from the IRSR Pays de la Loire Sleep Cohort were linked to health administrative data to identify proxies of heathy behaviors (HB) including adherence to cardiovascular (CV) drugs (medication possession ratio, [MPR]), cancer screening tests, influenza vaccination, alcohol and smoking consumption, and drowsiness-related road accidents during the two years preceding PAP onset in OSA patients. Multivariable regression analyses were conducted to evaluate the association of HB with subsequent PAP adherence. Healthcare resource use was evaluated according to subsequent PAP adherence. FINDINGS: We included 2,836 patients who had started PAP therapy between 2012 and 2018 (65% of whom were PAP adherent with mean daily use ≥4h/night). Being adherent to CV active drugs (MPR≥80%) and non-smoker were associated with a higher likelihood of PAP adherence (odds ratio, OR [95% confidence interval]: 1.43 [1.15; 1.77] and 1.37 [1.10; 1.71] respectively). Patients with no history of drowsiness-related road accidents were more likely to continue PAP (OR: 1.39 [1.04; 1.87]). PAP adherent patients used less healthcare resources 2 years before PAP initiation, than non-adherents (mean number of outpatient consultations: 19.0 vs 17.2, P=.003; hospitalization days: 5.7 vs 5.0, P=.04; emergency room visit: 30.7 vs 24.0% P=.0002). INTERPRETATION: Patients who adhere to PAP therapy of OSA were more health seeking and less healthcare users prior to device initiation than non-adherent patients. Until the HAE associated with PAP adherence is better understood, caution is warranted when interpreting the association of PAP adherence with CV health outcomes and healthcare resource use in non-randomized cohorts.

On punctate white matter lesions in preterm infants: Is ultrasound diagnosis feasible?

OBJECTIVES: To observe hyperechoic nodular or punctate white matter lesions (HNPL) in a population of preterm infants using routine cranial ultrasound (cUS), to describe the characteristics of HNPL, and to compare them with punctate white matter lesions (PWML) detected in magnetic resonance imaging (MRI). DESIGN: Retrospective observational single-center cohort study. SETTING: Level 2B neonatal unit in France. PATIENTS: 307 infants born <33 weeks gestation undergoing routine cUS with a total of 961 cUS performed. MAIN OUTCOME MEASURES: Description of lesions (HNPL/PWML): presence or absence, number, size, location, and structural distribution. RESULTS: Among the 307 included infants, 63 (20.5%) had at least one cerebral lesion, with 453 HNPL for 63 infants. HNPL were numerous (more than three in 66.6% of cases), primarily grouped in clusters (76.2%), located near the lateral ventricles (96.8%), and measuring more than 2 mm (79%). HNPL were diagnosed on day 29 on average and persisted until term. Overall, 43 MRI were performed in 307 infants, on average 18.9 days after last cUS, in 21 of those the indication was presence of HPNL on cUS. Of these 21 MRI, 14/21 presented 118 PWML compared to 173 HNPL on cUS. In the remaining MRI (7/21), no PWML were detected compared to 47 HNPL on cUS. CONCLUSIONS: In our population of 307 preterm infants, cUS allowed the diagnosis of HNPL, with a large similarity to PWML in MRI and a better sensitivity. But in the absence of data on inter-observer variability, we cannot exclude overdiagnosis of HNPL.

A Comparative Multicenter Cohort Study Evaluating the Long-Term Influence of the Strict Lockdown during the First COVID-19 Wave on Lung Cancer Patients (ARTEMISIA Trial).

The consequences of the strict health restrictions during the first wave of COVID-19 on lung cancer (LC) patients are not known. This cohort study evaluated the impact of the initial lockdown on management of and long-term outcome in LC patients. This exposed-unexposed-type study included two evaluation periods of 6 months each in non-selected patients; one began on the first day of lockdown in 2020, and the other in 2019 during the same calendar period. Various indicators were compared: clinical profiles, management delays and overall survival beyond 2 years. A total of 816 patients from 7 public or private centers were enrolled. The clinical characteristics of the patients in 2020 did not differ from those in 2019, except that the population was older (p = 0.002) with more non-smokers (p = 0.006). Delays for pre-therapeutic medical management were generally reduced after the first imaging in 2020 (1.28 [1.1-1.49]). In the multivariate analysis, being part of the 2020 cohort was correlated with better prognosis (HR = 0.71 [0.5-0.84], p < 0.001). The gain observed in 2020 mainly benefited non-smoking patients, along with ECOG PS 0-2 (p = 0.01), stage 4 (p = 0.003), squamous cell carcinoma (p = 0.03) and receiving systemic therapy (p = 0.03). In conclusion, the first lockdown did not exert any deleterious impact on LC patients.

Health-related behavioral changes during the COVID-19 pandemic. A comparison between cohorts of French and Italian university students.

This cross-sectional observational study compares the health behaviors of university students in France and Italy, examining how their choices and lifestyles were affected by the COVID-19 pandemic with the aim of contributing to the development of adequate public health and higher education institutions interventions. The French cohort was investigated between January and February 2022, while the Italian cohort was examined between March and April 2022. In both contexts, data were collected through web surveys using institutional directories of university degree programs. Data were collected using standardized tools, validated and recovered in full or partial form. The tool used consisted of three specific sections (general experience, eating habits, physical activity), to which a fourth, dedicated to describing the sociographic picture of the respondents, was added. It was found that the pandemic mainly affected the mental health and sense of well-being of young people in both countries. The pandemic altered dietary habits (41.8% of the French subjects and 38.3% of the Italians declared an increasing of their food intake), alcohol consumption (9.0% of the Italian respondents and 4.0% of the French respondents reported an increased alcohol consumption), propensity to smoke (among the French 85.3% subjects remained non-smokers versus 65.3% of the Italian subjects), sleep quality (25.7% of Italian students 16.6% of French students experienced a decline in the quality of their sleep), and physical activity levels (the percentage of physically active French subjects rose to 72.4%, whereas among Italian students, it dropped to 68,4%). The results emphasize the need for the implementation of relational and psychological interventions, even digital, to face the consequences of social isolation and negative changes in everyday behaviors due to the restrictions during the COVID-19 pandemic.

Is hybrid cardiac rehabilitation superior to traditional cardiac rehabilitation?

BACKGROUND: The current COVID-19 pandemic imposes changes in the management of cardiac pathologies. Cardiac rehabilitation needs to define new protocols to welcome patients back. In connection with the observations of the European Association of Preventive Cardiology, the choice of cardiac tele-rehabilitation appeared to be unavoidable. AIM: This retrospective research based on data from the Program for the Medicalisation of Information Systems (PMSI) and the electronic medical record analyzes the effect of Hybrid Cardiac Rehabilitation. METHODS: One hundred and ninety-two patients (29 females and 163 males) with an average of 56.9 years old (±10.3) were able to benefit from a Hybrid Cardiac Rehabilitation program. The data concerning the Stress Test and the Wall Squat Test were collected. RESULTS: We have noticed that patients had improved their cardiorespiratory capacity on the initial and final Stress Test 6.6 (±1.8) MET to 8.2 (±1.9) MET (p < 0.0001). We also found that patients improved lower limb muscle strength 75.1 (±44.8) seconds to 105.7 (±49.7) seconds (p < 0.0001). CONCLUSIONS: Hybrid Cardiac Rehabilitation protocols can be set up in this pandemic situation. The programme effectiveness appears to be comparable to the traditional model. However, additional studies are needed to determine the effectiveness of this programme in the long term.

Positive Airway Pressure Adherence, Mortality, and Cardiovascular Events in Patients with Sleep Apnea.

Rationale: Randomized controlled trials showed no effect of positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) on cardiovascular (CV) risk. However, patient selection and low PAP adherence preclude the generalization of their data to clinical samples. Objectives: To evaluate the association between hours of PAP use, mortality, and CV morbidity in real-life conditions. Methods: Data from the Pays de la Loire Cohort were linked to health administrative data to identify incident major adverse cardiovascular events (MACEs; a composite outcome of mortality, stroke, and cardiac diseases) in patients with OSA who were prescribed PAP. Cox proportional hazards analyses were conducted to evaluate the association between MACEs and quartiles of average daily PAP use over the study period. Measurements and Main Results: After a median follow-up of 6.6 years, 961 of 5,138 patients experienced MACEs. Considering nonadherent patients (0-4 h/night) as the reference group, adjusted hazard ratios (95% confidence intervals) for MACEs were 0.87 (0.73-1.04) for the 4-6 h/night group, 0.75 (0.62-0.92) for the 6-7 h/night group, and 0.78 (0.65-0.93) for the ⩾7 h/night group (P = 0.0130). Sensitivity analyses using causal inference approaches confirmed the association of PAP use with MACEs. The association was stronger in male patients (P value for interaction = 0.0004), patients without overt CV disease at diagnosis (P < 0.0001), and those belonging to the excessively sleepy symptom subtype (P = 0.060). Conclusions: These real-life clinical data demonstrate a dose-response relationship between PAP adherence and incident MACEs in OSA. Patient support programs may help improve PAP adherence and CV outcomes in patients with OSA.

Cancer risk in patients with sleep apnoea following adherent 5-year CPAP therapy.

BACKGROUND: Increasing evidence suggests that obstructive sleep apnoea (OSA) contributes to cancer risk; however, limited data are available on the impact of continuous positive airway pressure (CPAP) therapy on cancer incidence. We aimed to determine whether adherence to CPAP therapy is associated with a reduction in all-cancer incidence compared with nonadherent patients with OSA. METHODS: The study relied on data collected by the multicentre Pays de la Loire Sleep Cohort study, linked to health administrative data, so as to identify new-onset cancer. We included patients who were prescribed CPAP for OSA, with no history of cancer before the diagnostic sleep study or during the first year of CPAP. Patients with documented CPAP use for ≥4 h per night were defined as adherent. Those who discontinued or used CPAP <4 h per night constituted the nonadherent group. A propensity score inverse probability of treatment weighting analysis was performed to assess the effect of CPAP adherence on cancer risk. RESULTS: After a median (interquartile range) follow-up of 5.4 (3.1-8.0) years, 437 (9.7%) out of 4499 patients developed cancer: 194 (10.7%) in the nonadherent group (n=1817) and 243 (9.1%) in adherent patients (n=2682). The final weighted model showed no significant impact of CPAP adherence on all-cause cancer risk (subdistribution hazard ratio 0.94, 95% CI 0.78-1.14). CONCLUSIONS: Adherence to CPAP therapy in OSA patients was not associated with a reduction in all-cancer incidence. Whether adherent CPAP therapy of OSA might reduce the risk of specific cancer sites should be further evaluated.

The Effect of Social Isolation on Physical Activity during the COVID-19 Pandemic in France.

The objective of this cross-sectional study is to analyze the changes in physical activity (PA) practice of a sample of 2099 French adults, mostly females, who answered an online questionnaire during the first COVID-19 lockdown (March-May 2020). A descriptive analysis of participants was performed using relative frequencies. Chi-squared tests were performed to compare the responses of selected variables. Multinomial logistic regressions were performed to compare the variations of PA with all the variables identified. The age of participants ranged from 18 to 88. Among people who practiced PAs before the first lockdown, the probability to keep practicing PAs is higher among those with a lower level of education, among housewives and retirees and among those who lived in cities of 10,000-19,999 inhabitants. For those who did not practice PAs before the social distancing, the probability of starting to practice is greater in those with a lower level of education and for those who suffered from a chronic disease. Our results place the emphasis on the complexity and multifactoriality of the changes that emerged during the first lockdown. The "education" factor emerges, as a significant determinant of PA that should certainly be explored further.

Photoprotection of the Skin from Visible Light‒Induced Pigmentation: Current Testing Methods and Proposed Harmonization.

Visible light (VL) can induce pigmentary alterations, especially in dark-skinned individuals, and exacerbate photodermatoses and pigmentary disorders. Currently, there is no standardized method for assessing sunscreen protection against VL. On the basis of a critical review of published in vitro and in vivo methods, a VL photoprotection assessment method based on pigmentation is proposed.

[Care and follow-up of cardiovascular disease in women]. / Prise en charge et suivi de la pathologie cardio-vasculaire chez la femme.

The condition of women has vastly improved over recent decades: respect of equality, better salary conditions and health status. Although women, like men, are living longer, certain differences in care are emerging. This survey studies the characteristics of women's cardiovascular health, especially in terms of treatment and follow-up.

Estimated physical fitness and sociability: an interdisciplinary pilot study among French students.

BACKGROUND: The aim of this pilot study is to explore the main social factors influencing estimated physical fitness. METHODS: During the academic year of 2014/2015, 909 students from two French universities of the Hauts-de-France region completed a study including standardized anonymous self-reported questionnaires. Data were related to age, sex, social class, physical activity, social life and sociability. Physical fitness estimation was assessed through a validated VO2max questionnaire. RESULTS: A total of 749 17- to 24-year-old students were included. The mean age was 19.58. The sample was composed mainly of girls (59.68%). The mean estimated VO2max was 39.30±2.29 for males and 32.79±2.56 for girls. Some significant dependence and risk factors were found between estimated PF and some sociocultural aspects. CONCLUSIONS: Our study shows the importance of the socialization environment. The role, the age and the employment status of the parents are significant as they are a reference for the practice of sports and physical activities. The level of independence and sociability is strongly correlated to estimated physical fitness. These findings stress the need to develop a more holistic study, based on comprehensive and interdisciplinary approaches.

A CPAP data-based algorithm for automatic early prediction of therapy adherence.

OBJECTIVE: Adherence is a critical issue in the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP). Approximately 40% of patients treated with CPAP are at risk of discontinuation or insufficient use (< 4 h/night). Assuming that the first few days on CPAP are critical for continued treatment, we tested the predictive value at day 14 (D14) of the Philips Adherence Profiler™ (AP) algorithm for adherence at 3 months (D90). METHOD: The AP™ algorithm uses CPAP machine data hosted in the database of EncoreAnywhere™. This retrospective study involved 457 patients (66% men, 60.0 ± 11.9 years; BMI = 31.2 ± 5.9 kg/m2; AHI = 37.8 ± 19.2; Epworth score = 10.0 ± 4.8) from the Pays de la Loire Sleep Cohort. At D90, 88% of the patients were adherent as defined by a mean daily CPAP use of ≥ 4 h. RESULTS: In a univariate analysis, the factors significantly associated with CPAP adherence at D90 were older age, lower BMI, CPAP adherence (≥ 4 h/night) at D14, and AP™ prediction at D14. In a multivariate analysis, only older age (OR 2.10 [1.29-3.41], p = 0.003) and the AP™ prediction at D14 (OR 16.99 [7.26-39.75], p < 0.0001) were significant predictors. CPAP adherence at D90 was not associated with device-derived residual events, nor with the levels of pressure or leakage except in the case of very significant leakage when it persisted for 90 days. CONCLUSION: Automatic telemonitoring algorithms are relevant tools for early prediction of CPAP therapy adherence and may make it possible to focus therapeutic follow-up efforts on patients who are at risk of non-adherence.

Association Between Nocturnal Hypoxemia and Cancer Incidence in Patients Investigated for OSA: Data From a Large Multicenter French Cohort.

BACKGROUND: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans. RESEARCH QUESTION: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA? STUDY DESIGN AND METHODS: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia. RESULTS: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies. INTERPRETATION: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.

Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI-Evidence from in vitro and in vivo models.

Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy-ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the ß-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 µM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving µM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.

Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial.

PURPOSE: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. PATIENTS AND METHODS: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. RESULTS: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. CONCLUSIONS: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.

Linear and exponential sunscreen behaviours as an explanation for observed discrepancies in sun protection factor testing.

BACKGROUND: In vivo testing of sun protection factor (SPF) values can show considerable interlaboratory variability. We studied the underlying reasons and clinical implications. METHODS: Following the ISO 24444:2010 SPF testing method, seven contract research organizations (CROs) tested eight sunscreens marketed as SPF50 or SPF50+ and the reference SPF15 sunscreens P2 and P3 and SPF43 P6. We analysed differences in the products and CRO testing methods with regard to SPF variability. We tested the erythema prevention capacity of five of the products in subjects exposed to high doses of natural sunlight in Mauritius. RESULTS: Sun protection factor values varied dramatically between different CROs for some, but not all of the sunscreens. Those with the largest variability had an SPF50+, and their SPF values differed from a maximum of 62.4 to a minimum of 5.5. These products did not share a common sun-filter composition, and some CROs used low and others high irradiation dose regimens. When comparing these two regimens, test products fell into two categories: (i) they either behaved similarly ("linear") or (ii) they behaved differently ("exponential"). In the outdoor clinical study, exponential and linear sunscreens did not differ in their photoprotection capacities. CONCLUSION: Differences in reported SPF values depend on the linear vs exponential behaviour of such products if subjected to low- vs high-dose test regimens. Under real-time exposure to natural sunlight, exponential and linear sunscreens did not differ in their erythema prevention capacity. Laboratory SPF testing of exponential sunscreens bears the risk of underestimating their in-use SPF.

Phase II Study Evaluating the Mechanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR-mutated Non-pretreated Advanced Lung Cancer Receiving Osimertinib Until and Beyond Radiologic Progression: The MELROSE Trial.

BACKGROUND: Osimertinib, a third-generation tyrosine kinase inhibitor, is a new therapeutic option in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The tumor escape mechanisms after first-line treatment with osimertinib are partially known; most of the data being obtained by analysis of circulating tumor DNA (ctDNA) from the FLAURA phase III trial. STUDY DESIGN: The MELROSE study, a French multicentric, open label, phase II trial (ClinicalTrials.govNCT03865511) plans to enroll 150 patients with treatment-naive advanced EGFR-mutated (L858R or exon 19 deletion) NSCLC, age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status 0 or 1. All patients will receive osimertinib at the dose of 80 mg/d. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria will be performed every 3 months, with brain and thoracoabdominal computed tomographic scan. The continuation of osimertinib is at the discretion of the referring physician, particularly if clinical benefit is observed. The primary objective is the genetic tumor profile, both on tissue biopsy and ctDNA analyses, at the time of disease progression. Other endpoints include kinetic studies of ctDNA, biological progression-free survival (bPFS) (time from first study dose to first biological event on ctDNA), median PFS according to RECIST criteria 1.1 (called radiological [r] PFS), and median clinical (c) PFS (time from the first study dose to off-osimertinib). This study started in April 2019, and 18 centers in France are participants.

Density measurement of liquid 22MnB5 by aerodynamic levitation.

This study is part of the general context of thermophysical characterization of liquid metals with an aerodynamic levitation device and laser heating. The density measurements vs temperature of pure and alloyed metals are determined during cooling of the sample. The temperature and shape of the sample are measured, respectively, with a bichromatic pyrometer and filmed by a high-speed camera. The sample visualization is performed by backlighting, which has been preferred to self-illumination. The post-treatment process consists in a binarisation of each recorded image, and then, an ellipse is fitted on the detected edge. The density is directly calculated with the ellipse volume and the sample weight. The good agreement of experimental results on pure metals with the literature validates the method. Then, an industrial steel of unknown liquid density is characterized from 1750 K to 2250 K.

Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORγt.

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORγt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORγt+ cells, and inhibition of RORγt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.