Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in Patients With Respiratory Failure Due to COVID-19: The SOHO-COVID Randomized Clinical Trial.

Importance: The benefit of high-flow nasal cannula oxygen (high-flow oxygen) in terms of intubation and mortality in patients with respiratory failure due to COVID-19 is controversial. Objective: To determine whether the use of high-flow oxygen, compared with standard oxygen, could reduce the rate of mortality at day 28 in patients with respiratory failure due to COVID-19 admitted in intensive care units (ICUs). Design, Setting, and Participants: The SOHO-COVID randomized clinical trial was conducted in 34 ICUs in France and included 711 patients with respiratory failure due to COVID-19 and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen equal to or below 200 mm Hg. It was an ancillary trial of the ongoing original SOHO randomized clinical trial, which was designed to include patients with acute hypoxemic respiratory failure from all causes. Patients were enrolled from January to December 2021; final follow-up occurred on March 5, 2022. Interventions: Patients were randomly assigned to receive high-flow oxygen (n = 357) or standard oxygen delivered through a nonrebreathing mask initially set at a 10-L/min minimum (n = 354). Main Outcomes and Measures: The primary outcome was mortality at day 28. There were 13 secondary outcomes, including the proportion of patients requiring intubation, number of ventilator-free days at day 28, mortality at day 90, mortality and length of stay in the ICU, and adverse events. Results: Among the 782 randomized patients, 711 patients with respiratory failure due to COVID-19 were included in the analysis (mean [SD] age, 61 [12] years; 214 women [30%]). The mortality rate at day 28 was 10% (36/357) with high-flow oxygen and 11% (40/354) with standard oxygen (absolute difference, -1.2% [95% CI, -5.8% to 3.4%]; P = .60). Of 13 prespecified secondary outcomes, 12 showed no significant difference including in length of stay and mortality in the ICU and in mortality up until day 90. The intubation rate was significantly lower with high-flow oxygen than with standard oxygen (45% [160/357] vs 53% [186/354]; absolute difference, -7.7% [95% CI, -14.9% to -0.4%]; P = .04). The number of ventilator-free days at day 28 was not significantly different between groups (median, 28 [IQR, 11-28] vs 23 [IQR, 10-28] days; absolute difference, 0.5 days [95% CI, -7.7 to 9.1]; P = .07). The most common adverse events were ventilator-associated pneumonia, occurring in 58% (93/160) in the high-flow oxygen group and 53% (99/186) in the standard oxygen group. Conclusions and Relevance: Among patients with respiratory failure due to COVID-19, high-flow nasal cannula oxygen, compared with standard oxygen therapy, did not significantly reduce 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT04468126.

Italian results of the PRECONNECT study: safety and efficacy of trifluridine/tipiracil in metastatic colorectal cancer.

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0-1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients.

Lay abstract PRECONNECT is an international study demonstrating the efficacy and tolerability of the drug combination trifluridine/tipiracil in adult patients with metastatic colorectal cancer treated in everyday clinical practice. For this publication, the authors conducted an analysis performed on the 161 Italian patients enrolled in this study. These kinds of analyses are important because of the differences that may arise across different countries. The most common contraindications were not dangerous to health. Furthermore, 3 months from beginning the medication, half of the patients did not show a worsening of the disease and quality of life during treatment was maintained. Clinical trial registration: NCT03306394 (ClinicalTrials.gov).

Who venerated the ancestors at the Petit-Chasseur site? Examining Early Bronze Age cultic activities around megalithic monuments through the archaeometric analyses of ceramic findings (Upper Rhône Valley, Switzerland, 2200-1600 BC).

Through the analyses of recovered pottery, this study explores the social dimension of an ancestor cult developed at the Petit-Chasseur megalithic necropolis (Upper Rhône Valley, Switzerland) during the Early Bronze Age (2200-1600 BC). The jar votive offerings and domestic pottery from settlement sites were characterized using a range of spectroscopic and microscopic techniques. Acquired archaeometric data allowed identification of six ceramic fabrics and two types of clay substrate-illite- and muscovite-based-which were used in pottery production. The present article discusses the pottery composition in the light of natural resources available in the region, thus shedding light on raw material choices and paste preparation recipes. The Early Bronze Age people that lived in the Upper Rhône Valley seem to have shared a common ceramic tradition, partly inherited from the previous Bell Beaker populations. The compositional correspondence between the jar offerings and domestic pottery revealed that the majority of the known Early Bronze Age groups partook in cultic activities at the Petit-Chasseur megalithic necropolis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12520-023-01737-0.

Measuring pelvises in 3D surface scans and in MDCT generated virtual environment: Considerations for applications in the forensic context.

Virtual Anthropology (VA) transposes the traditional methods of physical anthropology to virtual environments using imaging techniques and exploits imaging technologies to devise new methodological protocols. In this research, we investigate whether the measurements used in the Diagnose Sexuelle Probabiliste (DSP) and Ischio-Pubic Index (IPI) differ significantly when 3D models of a bone are generated using 3D surface scans (3DSS) and Multidetector Computed Tomography (MDCT) scans. Thirty pelvises were selected from the SIMON identified skeletal collection. An equal ratio of females to males was sought, as well as a good preservation of the bones. The pelvises were scanned using an MDCT scanner and a 3D surface scanner. The measurements of the DSP and IPI methods on the dry bones (referred to as macroscopic measurements here), and then to the 3D models. The intra- and interobserver, using the Technical Error of Measurement (TEM) and relative Technical Error of Measurement (rTEM) error was assessed, and we aimed to observe if the measurements made on the MDCT and 3DSS generated models were significantly different from those taken on the dry bones. Additionally, the normality of the data was tested (Shapiro-Wilk test) and the differences in measurements was evaluated using parametric (Student t-tests) and non-parametric (Wilcoxon) tests. The TEM and rTEM calculations show high intra and interobserver consistency in general. However, some measurements present insufficient inter- and intraobserver agreement. Student t and Wilcoxon tests indicate potentially significant differences of some measurements between the different environments. The results show that especially in the virtual environment, it is not easy to find the right angle for some of the DSP measurements, However, when comparing the measurement differences between dry and virtual bones, the results show that most of the differences are less than or equal to 2.5 mm. Considering the IPI, the landmarks are already difficult to determine on the dry bone, but they are even more difficult to locate in the virtual environment. Nevertheless, this study shows that quantitative methods may be better suited for application in the virtual environment, but further research using different methods is needed.

Validation of surface plasmon resonance screening of a diverse chemical library for the discovery of protein tyrosine phosphatase 1b binders.

We investigated the suitability of surface plasmon resonance (SPR) for providing quantitative binding information from direct screening of a chemical library on protein tyrosine phosphatase 1b (PTP1B). The experimental design was established from simulations to detect binding with K(D) < 10⁻4 M. The 1120 compounds (cpds) were injected sequentially at concentrations [C(cpd)] of 0.5 or 10 µM over various target surfaces. An optimized evaluation procedure was applied. More than 90% of cpds showed no detectable signal in four screens. The 30 highest responders at C(cpd)=10 µM, of which 25 were selected in at least one of three screens at C(cpd)=0.5 µM, contained 22 promiscuous binders and 8 potential PTP1B-specific binders with K(D) ~10⁻5 M. Inhibition of PTP1B activity was assayed and confirmed for 6 of these, including sanguinarine, a known PTP1B inhibitor. C(cpd) dependence studies fully confirmed screening conclusions. The quantitative consistency of SPR data led us to propose a structure-activity relationship (SAR) model for developing selective PTP1B inhibitors based on the ranking of 10 arylbutylpiperidine analogs.

Titanium dioxide nanoparticles disturb the fibronectin-mediated adhesion and spreading of pre-osteoblastic cells.

In the context of rapid development of nanoparticles (NPs) for industrial applications, the question of their toxicity and biological effects must be considered. In this work, we have assessed the influence of titanium dioxide NPs on the adhesion and spreading of MC-3T3 pre-osteoblasts by using a cell subclone that does not produce its own extracellular matrix. Petri dishes were coated with the important adhesion protein fibronectin (Fn). By incubating these Fn-coated surfaces with different amounts of TiO(2) NPs, we have shown that the adhesion of pre-osteoblasts is disturbed, with an important decrease in the number of adherent cells (from 40 to 75% depending upon the concentration and type of NPs). Petri-dish surfaces were analyzed with environmental scanning electron microscropy (ESEM), with images showing that TiO(2) NP aggregates are bound to the layer of adsorbed Fn molecules. The cells cultured on these Fn/NP surfaces adopted an irregular shape and an aberrant organization of actin cytoskeleton, as revealed by fluorescence microscopy. Most importantly, these results, taken together, have revealed that the actin cytoskeleton forms abnormal aggregates, even on top of the nucleus, that coincide with the presence of large aggregates of NPs on top of cells. On the basis of these observations, we propose that some Fn molecules are able to desorb from the Petri dish surface to coat TiO(2) NPs. Fn/NP complexes are not attached firmly enough on the surface to allow for normal cell adhesion/spreading and the development of tense actin fibers. These results stress the paramount need for the assessment of the toxicology of NPs, with special attention to their interactions with biomolecules.

Immunoglobulin A Vasculitis Following COVID-19: A French Multicenter Case Series.

OBJECTIVE: Immunoglobulin A vasculitis (IgAV) usually occurs following viral respiratory tract infection. In the context of the global coronavirus disease 2019 (COVID-19) pandemic, we describe a case series of patients who developed IgAV following SARS-CoV-2 infection. METHODS: This national multicenter retrospective study included patients with IgAV following SARS-CoV-2 infection from January 1, 2020, to January 1, 2022. Patients had histologically proven IgAV and reverse transcription PCR (RT-PCR)-proven SARS-CoV-2 infection. The interval between infection and vasculitis onset had to be < 4 weeks. RESULTS: We included 5 patients, 4 of whom were women with a mean age of 45 years. Four patients had paucisymptomatic infections and 1 required a 48-hour low-flow oxygen treatment. All 5 patients had purpuric skin involvement. Arthritis was observed in 2 patients, 3 had IgA glomerulonephritis, and 2 had digestive involvement. Three renal biopsies were performed and showed mesangial IgA deposits without any extracapillary proliferation. Median C-reactive protein was 180 (range 15.1-225) mg/L, median serum creatinine level was 65 (range 41-169) µmol/L, and 2 patients had a glomerular filtration rate < 60 mL/min. Four patients received first-line treatment with glucocorticoids. All patients had a favorable progression and 2 patients experienced minor skin relapses, one after COVID-19 vaccination. CONCLUSION: This series describes the emergence of IgAV closely following COVID-19; we were not able to eliminate an incidental link between these events. Their disease outcomes were favorable. In most of our patients, the SARS-CoV-2 infection was paucisymptomatic, and we recommend RT-PCR tests to look for COVID-19 in patients without any evident triggers for IgAV.

Testing the validity of population-specific sex estimation equations: An evaluation based on talus and patella measurements.

Sex estimation is essential for forensic scientists to identify human skeletal remains. However, the most sexually dimorphic elements like pelvis or skull are not always assessable. Osteometric analyses have proven useful in sex estimation, but also to be population specific. The main purpose of this study was to test the validity of contemporary Greek and Spanish discriminant functions for the talus and the patella, respectively, on a Swiss skeletal sample and to quantify the utility of the measurements as a novel approach in osteometric sex assessment. Four talus and three patella measurements on dry bone were obtained from 234 individuals of the modern cemetery SIMON Identified Skeletal Collection. The previously derived discriminant functions were applied, accuracies determined, the utility of the different measurements was assessed and new multivariable equations constructed. Accuracies varied between 67% and 86% for talus and 63% and 84% for patella, similar to those reported by the original studies. Multivariable equations should be preferred over equations based on single measurements and combining the most significant measurements rather than using several variables obtained the best possible accuracy. The new discriminant functions did not provide a substantial improvement to the original ones. The overall utility of talus and patella is limited, allowing sex estimation with sufficient certainty only in a small proportion of individuals. Discriminant functions developed in contemporary Greek or Spanish populations are in principle applicable also to Swiss contemporary populations. We recommend that at present existent studies of this type should be validated and tested rather than developing new formulas.

Bronze Age innovations and impact on human diet: A multi-isotopic and multi-proxy study of western Switzerland.

The archaeological Bronze Age record in Europe reveals unprecedented changes in subsistence strategies due to innovative farming techniques and new crop cultivation. Increasing cultural exchanges affected the economic system. The inhabitants of Switzerland played a pivotal role in this European context through relationships with the Mediterranean, the High and Middle Danube regions and the Alps thanks to the area's central position. This research aims to reconstruct, for the first time in Switzerland, human socio-economic systems through the study of human diet, herding and farming practices and their changes throughout the Bronze Age (2200-800 BCE) by means of biochemical markers. The study includes 41 human, 22 terrestrial and aquatic animal specimens and 30 charred seeds and chaff samples from sites in western Switzerland. Stable isotope analyses were performed on cereal and legume seeds (δ13C, δ15N), animal bone collagen (δ13Ccoll, δ15N, δ34S), human bone and tooth dentine collagen (δ13Ccoll, δ15N,) and human tooth enamel (δ13Cenamel). The isotopic data suggest a) an intensification of soil fertilization and no hydric stress throughout the Bronze Age, b) a human diet mainly composed of terrestrial resources despite the proximity of Lake Geneva and the Rhone river, c) a diet based on C3 plants during the Early and Middle Bronze Age as opposed to the significant consumption of 13C-enriched resources (probably millet) by individuals from the Final Bronze Age, d) no important changes in dietary patterns throughout an individual's lifespan but a more varied diet in childhood compared to adulthood, e) no differences in diet according to biological criteria (age, sex) or funerary behavior (burial architecture, grave goods).

RANKL-Induced Increase in Cathepsin K Levels Restricts Cortical Expansion in a Periostin-Dependent Fashion: A Potential New Mechanism of Bone Fragility.

Receptor activator of nuclear factor-κΒ ligand (RANKL) is necessary and sufficient to promote osteoclastogenesis and a key pathogenic factor in osteoporosis. Failure of periosteal apposition to compensate for bone loss due to endosteal resorption further contributes to bone fragility. Whether these two processes are biologically related, however, remains unknown. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we first examined cortical bone parameters at distal radius and tibia in postmenopausal women (PMW) as well as in cadaveric human adult humeri. Increases in medullary area were negatively correlated with cortical bone volume but positively with total bone volume, and this relationship was stronger in the dominant arm, suggesting a mechanically driven process. To investigate the role of RANKL in this dual process, we used mice overexpressing huRANKL (huRANKLTg+ ). Trabecular and cortical bone volume (Ct.BV) are reduced in these mice, whereas cortical total volume (Ct.TV) is increased. In these bones, Sost mRNA levels are downregulated and periostin (Postn) mRNA levels upregulated, hence providing a positive message for periosteal bone formation. In turn, genetic deletion of Postn in huRANKLTg+  mice prevented the increase in Ct.TV and aggravated bone fragility. In contrast, cathepsin K (Ctsk) ablation improved Ct.TV in both huRANKLTg+  and wild-type (WT) mice and stimulated periosteal bone formation, while augmenting Postn protein levels. Therefore, bone strength in huRANKLTg+ /Ctsk-/- mice was restored to WT levels. These findings suggest that high levels of RANKL not only induce endosteal bone loss but may somewhat restrict periosteal bone formation by triggering periostin degradation through cathepsin K, hence providing a biological mechanism for the observed limited increase in cortical area in postmenopausal women. © 2021 American Society for Bone and Mineral Research (ASBMR).

Lessons learned from COVID-19 for clinical research operations in Italy: what have we learned and what can we apply in the future?

The coronavirus disease 2019 (COVID-19) pandemic has stressed the importance of health research as never before. In the specific domain of clinical research, the effort to rapidly find responses to health challenges and therapeutic hypotheses has highlighted the need for efficient, timely, ethically correct research. The guidelines published by the Agenzia Italiana del Farmaco have shown that some useful changes are feasible: simple and rapid methods have been implemented to conduct clinical research in the emergency conditions of the pandemic, maintaining high levels of quality. In this perspective, four Italian scientific associations operating in clinical research have worked together to evaluate which measures, among the ones implemented during the pandemic, have been particularly significant and potentially effective under normal conditions or in case of emergencies, and that therefore will be useful in the future as well.

Ancient proteins provide evidence of dairy consumption in eastern Africa.

Consuming the milk of other species is a unique adaptation of Homo sapiens, with implications for health, birth spacing and evolution. Key questions nonetheless remain regarding the origins of dairying and its relationship to the genetically-determined ability to drink milk into adulthood through lactase persistence (LP). As a major centre of LP diversity, Africa is of significant interest to the evolution of dairying. Here we report proteomic evidence for milk consumption in ancient Africa. Using liquid chromatography tandem mass spectrometry (LC-MS/MS) we identify dairy proteins in human dental calculus from northeastern Africa, directly demonstrating milk consumption at least six millennia ago. Our findings indicate that pastoralist groups were drinking milk as soon as herding spread into eastern Africa, at a time when the genetic adaptation for milk digestion was absent or rare. Our study links LP status in specific ancient individuals with direct evidence for their consumption of dairy products.

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia.

BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.

Sustained Response and Rationale of Programmed Cell Death-1-Targeting for Progressive Multifocal Leukoencephalopathy.

In this study, we report a complete (clinical, radiological, and virological) sustained (1 year) response after nivolumab salvage therapy in a progressive multifocal leukoencephalopathy patient. Analyses of the cells infiltrate in a pretreatment brain biopsy suggest that parenchymal programmed cell death-L1+ macrophages could be the T-cells partnership in immune exhaustion and virus escape.

Preosteoblasts and fibroblasts respond differently to anatase titanium dioxide nanoparticles: a cytotoxicity and inflammation study.

There is a bundle of proofs suggesting that some industrial nanoparticles (NPs) can provoke diseases and pollute the environment durably. However, these issues still remain controversial. In the biomedical field, TiO(2) NPs were recently proposed to serve as fillers in polymeric materials to improve bone prostheses and scaffolds. Submicrometer TiO(2) particles could also result from wear debris of prostheses. Thus, it appears to be of the highest importance to elucidate the effects of well-characterized TiO(2) NPs on the behaviour of osteoblasts. In this work, we have measured the toxicity of anatase TiO(2) NPs with two different cell types, on L929 fibroblasts and for the first time on MC-3T3 pre-osteoblasts, with the aim to determine the level of cellular toxicity and inflammation. Our results clearly show that these NPs provoke different dose-response effects, with the pre-osteoblasts being much more sensitive than fibroblasts. Furthermore, we observed that anatase TiO(2) NPs had no effect on cell adhesion. By contrast, both cell types had their morphology and LDH release modified in the presence of NPs. Their DNA was also found to be fragmented as analyzed by quantifying the sub-G1 cell population with flow cytometry. By measuring the production of IL-6 and TNF-α proinflammatory cytokines, we have shown that TNF-α was never produced and that MC-3T3 cells were secreting IL-6. Most importantly, our results highlight the necessity of evaluating the toxicity of prostheses wear debris, and of NP coatings of medical implants, to determine if they can possibly provoke inflammation and inhibit bone reconstruction.