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The 1958 Delaney amendment to the Federal Food Drug and Cosmetics Act prohibited food additives causing cancer in animals by appropriate tests. Regulators responded by adopting chronic lifetime cancer tests in rodents, soon challenged as inappropriate, for they led to very inconsistent results depending on the subjective choice of animals, test design and conduct, and interpretive assumptions. Presently, decades of discussions and trials have come to conclude it is impossible to translate chronic animal data into verifiable prospects of cancer hazards and risks in humans. Such conclusion poses an existential crisis for official agencies in the US and abroad, which for some 65 years have used animal tests to justify massive regulations of alleged human cancer hazards, with aggregated costs of $trillions and without provable evidence of public health advantages. This article addresses suitable remedies for the US and potentially worldwide, by critically exploring the practices of regulatory agencies vis-á-vis essential criteria for validating scientific evidence. According to this analysis, regulations of alleged cancer hazards and risks have been and continue to be structured around arbitrary default assumptions at odds with basic scientific and legal tests of reliable evidence. Such practices raise a manifold ethical predicament for being incompatible with basic premises of the US Constitution, and with the ensuing public expectations of testable truth and transparency from government agencies. Potential remedies in the US include amendments to the US Administrative Procedures Act, preferably requiring agencies to justify regulations compliant with the Daubert opinion of the Daubert ruling of the US Supreme Court, which codifies the criteria defining reliable scientific evidence. International reverberations are bound to follow what remedial actions may be taken in the US, the origin of current world regulatory procedures to control alleged cancer causing agents.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): 2 Ludwig Boltzmann Institute for Cardiovascular Research. Background The European Society of Cardiology regularly updates its clinical practice guidelines. However, it is not well established whether guideline-changes have significant effects on actual clinical practice. Therefore, we retrospectively analyzed lipid therapy at discharge after acute coronary syndrome (ACS) in a one-year period until 3 months before and a one-year period starting 6 months after publication of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias, respectively. Methods and Results In total we included 702 patients that were discharged alive after treatment for ACS. 360 patients were treated in the period before and 342 were treated in the period after guideline change. 67.7 % of patients were male and 59.1% were treated for ST-elevation myocardial infarction (STEMI). After guideline change the proportion of patients that were discharged on high dose statin was significantly higher as compared to the period before the new guidelines were published (89.2 % vs 79.2 %; p=0.001). Ezetimibe was prescribed more often after the new guidelines (15.0 % vs 3.0 %; p Conclusions The update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias was associated with a significant improve in the proportion of high dose statin and ezetimibe treatment in patients after ACS resulting in a significant lower LDL plasma level in a subgroup of patients. The change of these guidelines rapidly translated into clinical practice resulting in improved risk factor control in high-risk patients.

Introduction COVID-19 is generally milder in children than in adults, however severe infection has been described in some patients. Few data are available on use of Remdesivir (RDV) in children, as most clinical trials focused on adult patients. We report a multicenter study to investigate the safety of RDV in children affected by COVID-19. Methods We collected the clinical data of children with COVID-19 treated with RDV between March 2020 and February 2022 in 10 Italian hospitals. Clinical data were compared according to the duration of RDV therapy. Linear and logistic regression models were used to determine the association of significant variables from the bivariate analysis to the duration of RDV therapy. Results A total of 50 patients were included, with a median age of 12.8 years. Many patients had at least one comorbidity (78%), mostly obesity. Symptoms were fever (88%), cough (74%) and dyspnea (68%). Most patients were diagnosed with pneumonia of either viral and/or bacterial etiology. Blood test showed leukopenia in 66% and increased C-reactive protein (CRP) levels in 63% of cases. Thirty-six patients received RDV for 5 days, nine patients up to 10 days. Most children who received RDV longer were admitted to the PICU (67%). Treatment with RDV was well tolerated with rare side effects (Table 1): bradycardia was recorded in 6% of cases, solved in less than 24 hours after discontinuation. A mild elevation of transaminases was observed in 26% of cases, however for the 8%, it was still detected before the RDV administration. Therefore, in these cases, we could not establish if it was caused by COVID-19, RDV o both. Patients who received RDV for more than 5 days waited longer for its administration after pneumonia diagnosis. The presence of comorbidities and the duration of O2 administration significantly correlated with the duration of RDV therapy at the linear regression analysis. Conclusion Our experience indicates that RDV against SARS-CoV-2 is safe and well-tolerated in pediatric populations at high risk of developing severe COVID-19. Our data suggest that delaying RDV therapy after diagnosis of pneumonia may be associated with a longer duration of antiviral therapy, especially in patients with comorbidities.

In the MEG II detector, the measurement of the momentum of the charged particle is performed by a high transparency single volume, full stereo cylindrical Drift Chamber (CDCH). It is composed by 9 concentric layers, each consisting of 192 drift cells. The single drift cell is approximately squared, with a 20 μm gold plate tungsten sense wire surrounded by 40 μm/50 μm silver plated aluminum field wires in a ratio of 5:1. During the construction of the first CDCH, we observed the breaking of about hundred cathode wires: 97 of these were 40 μm aluminum wires, while 10 were 50 μm wires. Since the number of broken cathodes is less than 1% of the total, one can expect the influence on the track reconstruction efficiency to be not so dramatic. We verified by means of simulations that the loss of one cathode does not change the cell electric field appreciably. Here we present the results of the analysis of the effects of mechanical stress and chemical corrosion observed on these broken wires. Finally, we show the studies carried out on new wires to overcome the weaknesses found and the process that will be used for the construction of the new drift chamber (CDCH2). It will be built with the same modular technique, as for the previous one, the use of the wiring robot will be optimized to improve some weaker step in the procedure, new wires will be adopted with a 25% thicker diameter, which has very little effects on the resolution and efficiency of the detector. Furthermore these wires are made with a manufacturing process different from that used previously.

International audience; SCCS (Scientific Committee on Consumer Safety), scientific opinion on Butylated hydroxytoluene (BHT), preliminary version of September 27, 2021, final version of December 2, 2021, SCCS/1636/21.

Background Treatment with monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) was found to reduce all-cause mortality in addition to cardiovascular events, suggesting pleiotropic effects. Eicosanoids are bioactive metabolites involved in cardiovascular disease and have not yet been studied in the course of PCSK9 inhibition. Methods In this prospective translational single-center study, plasma samples were collected from 64 patients before and after initiation of PCSK9 inhibitor treatment. Metabolomic analyses were performed using liquid chromatography coupled to high-resolution mass spectrometry. Results A total of 62 bioactive eicosanoids were detected. Among the metabolites, four were significantly decreased by PCSK9 inhibition after one month and remained stable after 6 months (figure): arachidonic acid (p=0.003), 12,13-DiHOME (p Conclusion PCSK9 inhibition leads to significant changes in the eicosanoid profile already after one month, in particular to a downregulation of arachidonic acid. This discovery complements the presumed pleiotropic effects of PCSK9 inhibition and may provide additional benefit in the treatment of atherosclerotic disease. Funding Acknowledgement Type of funding sources: None.

The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations.

The correct quantification of the dose released in charged particle therapy treatments requires the knowledge of the double differential fragmentation cross section of particles composing both the beam and the target. The FragmentatiOn Of Target (FOOT) experiment aims at measuring these cross sections for ions of interest for charged particle therapy applications. This article describes the performance of the time-of-flight (TOF)-wall detector of the experiment. The detector is composed of two layers of 44 cm $\times 2$ cm $\times 3$ mm plastic scintillator bars (20 for each layer), arranged orthogonally and read-out by silicon photomultipliers. The detector is designed to identify the charge of fragments ranging from protons to oxygen ions, with a maximum energy of 700 MeV/u, by measuring the energy released in the scintillators and the TOF with respect to a start counter. In this study, the detector was scanned with carbon ions of energy between 115 and 400 MeV/u and with a 60-MeV proton beam. The measurements show an energy resolution ( $\sigma _{E}/\mu _{E}$ ) between 6% and 4% and a contribution of the detector to the TOF system time resolution between 25 and 20 ps (standard deviation) for carbon ions and between 100 and 80 ps for protons.

ObjectivesTo evaluate the prevalence of carotid intima-media thickness and plaques in a cohort of persons living with HIV, the role of cardiovascular risk factors, the impact of the antiretroviral regimens, and the difference between naïve and experienced patients in the onset of carotid lesions.MethodsThis project was initiated in 2019 and involves eight Italian Centers. Carotid changes were detected using a power color-Doppler ultrasonography with 7.5 MHz probes. The following parameters are evaluated: intima-media thickness of both the right and left common and internal carotids: Data regarding risk factors for CVD, HIV viral load, CD4+ cell counts, serum lipids, glycaemia, and body mass index. The associations between pathological findings and potential risk factors were evaluated by logistical regression, with odds ratios (OR) and 95% confidence intervals (95% CI).ResultsAmong 1147 evaluated patients, aged 52 years on average, 347 (30.2%) had pathological findings (15.8% plaques and 14.5% IMT). Besides usual risk factors, such as older age, male sex, and dyslipidemia, CD4+ cell nadir ConclusionsOur data show that the overall percentage of carotid impairments nowadays remains high. Color-Doppler ultrasonography could play a pivotal role in identifying and quantifying atherosclerotic lesions among persons living with HIV, even at a very premature stage, and should be included in the algorithms of comorbidity management of these patients.

Aloe ferox Mill is widely used as a traditional herbal medicine for the treatment of a broad spectrum of illnesses given its laxative, anti-inflammatory, bitter tonic, anti-oxidant, antimicrobial and anti-cancer properties. Using the in vivo alkaline comet assay in animals (OECD 489), this study investigated the potential in vivo genotoxicity of dried Aloe ferox juice at dose levels of 500, 1000, and 2000 mg/kg/day in mice. Aloe ferox showed no genotoxic activity in preparations of single cells from the colon of the treated Hsd:ICR (CD-1) male mice. No statistically significant increase in DNA migration over the negative control was observed by analysis of variance for both comet parameters, tail moment and tail intensity, apart from the positive control ethyl methanesulphonate that induced clear and statistically significant increases in DNA migration parameters over the concurrent controls. The new reported scientific evidence unequivocally demonstrates that dried Aloe ferox juice containing hydroxyanthracene derivatives does not induce DNA damage in preparations of single cells from colon in in vivo comet genotoxicity studies. This suggests that the hyperplastic changes and mucosal hyperplasia observed after long-term administration of Aloe vera non-decolourised whole leaf extract may be attributed to an epigenetic effect of the material under investigation.

et al., Feedhorn- and orthomode transducer- (OMT) coupled transition edge sensor (TES) bolometers have been designed and micro-fabricated to meet the optical specifications of the LiteBIRD high frequency telescope (HFT) focal plane. We discuss the design and optical characterization of two LiteBIRD HFT detector types: dual-polarization, dual-frequency-band pixels with 195/280 GHz and 235/337 GHz band centers. Results show well-matched passbands between orthogonal polarization channels and frequency centers within 3% of the design values. The optical efficiency of each frequency channel is conservatively reported to be within the range 0.64−0.72, determined from the response to a cryogenic, temperature-controlled thermal source. These values are in good agreement with expectations and either exceed or are within 10% of the values used in the LiteBIRD sensitivity forecast. Lastly, we report a measurement of loss in Nb/SiNx/Nb microstrip at 100 mK and over the frequency range 200–350 GHz, which is comparable to values previously reported in the literature., This work is supported by NASA under grant no. 80NSSC18K0132.

The MEG experiment at the Paul Scherrer Institut (PSI) represents the state of the art in the search for the charged Lepton Flavor Violating μ+→e+γ decay, setting the most stringent upper limit on the BR(μ+→e+γ)≤4.2×10^-13 (90% C.L.). An upgrade of MEG, MEG II, was designed, commissioned and recently started the physics data taking. Its goal is to reach a sensitivity level of . In order to 6×10^-14 reconstruct the positron momentum vector a Cylindrical Drift CHamber (CDCH) with unprecedented peculiarities was built, featuring angular and momentum resolutions at the 6.5 mrad and 100 keV/c level. The CDCH is a 2-meter long, 60 cm in diameter, low-mass, single volume detector with high granularity: 9 layers of 192 drift cells, few mm wide, defined by wires in a stereo configuration for longitudinal hit localization. The filling gas mixture is Helium:Isobutane 90:10. The total radiation length is 1.5×10^-3 X0, thus minimizing the Multiple Coulomb Scattering and allowing for a single-hit resolution

We have developed a Superconducting Quantum Interference Device (SQUID) controller unit for Transition Edge Sensors (TES) readout, designed to be used in a space mission. The unit is made of 8 boards and each board can condition four SQUID array amplifiers. The board design is inspired by a similar one developed for ground based experiments, but specific changes have been made to adopt Components Off The Shelf (COTS) with space grade equivalents, to implement redundancy and cross-strapping capabilities. The design also includes the thermal path to lift the heat off the boards towards an in-house designed monolithic aluminum rack.

This chapter focuses on the role of advanced practice providers (APPs) in the context of emergency telehealth by describing one of the first successful programs, started in 2003, at the University of Mississippi Medical Center (UMMC). Important issues germane to developing a program to provide telehealth supervision to APPs are covered. Specific concerns addressed by UMMC as the program was developed are described and generalized to the current health care environment. Major considerations regarding delivery models, contracts, technology, rationale for using APPs, regulatory concerns, and educational preparation are also discussed.

Botanical safety science continues to evolve as new tools for risk assessment become available alongside continual desire by consumers for "natural" botanical ingredients in consumer products. Focusing on botanical food/dietary supplements a recent international roundtable meeting brought together scientists to discuss the needs, available tools, and ongoing data gaps in the botanical safety risk assessment process. Participants discussed the key elements of botanical safety evaluations. They provided perspective on the use of a decision tree methodology to conduct a robust risk assessment and concluded with alignment on a series of consensus statements. This discussion highlighted the strengths and vulnerabilities in common assumptions, and the participants shared additional perspective to ensure that this end-to-end safety approach is sufficient, actionable and timely. Critical areas and data gaps were identified as opportunities for future focus. These include, better context on history of use, systematic assessment of weight of evidence, use of in silico approaches, inclusion of threshold of toxicological concern considerations, individual substances/matrix interactions of plant constituents, assessing botanical-drug interactions and adaptations needed to apply to in vitro and in vivo pharmacokinetic modelling of botanical constituents.

Sex workers, including female ones, have a higher risk of developing cancer and oral diseases due to the overlapping of risk factors. To characterize oral health status and healthcare practices and behaviors in female sex workers. Both quantitative and qualitative concomitant approaches were used. A closed-ended questionnaire, clinical examination, and semi-structured interview were administered, from July 2017 to August 2018, to 21 intentionally selected participants, in the city of Itajai, southern Brazil. Although the participants reported having good oral health and healthcare habits, some oral diseases and harmful habits were observed. Poor oral hygiene and habits such as smoking, alcohol, and illicit drug use were found. Most of the participants had undergone gynecological follow-up in the last 12 months. Qualitative analysis gave rise to six categories: Social aspects of working as a sex worker, Work routine, Sexual practices and behaviors and protection from sexually transmitted infections, Practices and behaviors (including unprotected sun exposure, smoking, and alcohol use at work), Use of illicit drugs at work, and General and oral health care and perceptions about their oral health. Oral health status of the participants was variable, and most of them smoked cigarettes, drank alcohol, and consumed illicit drugs at work. Preventive condom use was reported. Most of them underwent recent serological tests for sexual diseases and gynecological follow-up, incentivized by the community health workers that facilitate access to public services.

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence &lt, 80%, and mainly occurred in APOBEC3-related sites. All MRMs persisted over-time in the 2 MODAt. C2-V3-C3 genetic-distance significantly changed from T1 to T3 in APACHE individuals (+0.36[0.11–0.41], p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap &gt, 70%) and genealogical sorting indices (GSI &gt, 0.50 with p-value &lt, 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.