BAL Proteomic Signature of Lung Adenocarcinoma in IPF Patients and Its Transposition in Serum Samples for Less Invasive Diagnostic Procedures

Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence suggests that IPF increases the risk of lung carcinogenesis. Both diseases show similarities in terms of risk factors, such as history of smoking, concomitant emphysema, and viral infections, besides sharing similar pathogenic pathways. Lung cancer (LC) diagnosis is often difficult in IPF patients because of the diffuse lung injuries and abnormalities due to the underlying fibrosis. This is reflected in the lack of optimal therapeutic strategies for patients with both diseases. For this purpose, we performed a proteomic study on bronchoalveolar lavage fluid (BALF) samples from IPF, LC associated with IPF (LC-IPF) patients, and healthy controls (CTRL). Molecular pathways involved in inflammation, immune response, lipid metabolism, and cell adhesion were found for the dysregulated proteins in LC-IPF, such as TTHY, APOA1, S10A9, RET4, GDIR1, and PROF1. The correlation test revealed a relationship between inflammation- and lipid metabolism-related proteins. PROF1 and S10A9, related to inflammation, were up-regulated in LC-IPF BAL and serum, while APOA1 and APOE linked to lipid metabolism, were highly abundant in IPF BAL and low abundant in IPF serum. Given the properties of cytokine/adipokine of the nicotinamide phosphoribosyltransferase, we also evaluated its serum abundance, highlighting its down-regulation in LC-IPF. Our retrospective analyses of BAL samples extrapolated some potential biomarkers of LC-IPF useful to improve the management of these contemporary pathologies. Their differential abundance in serum samples permits the measurement of these potential biomarkers with a less invasive procedure

Clinical longevity of direct and indirect posterior resin composite restorations: an updated systematic review and meta-analysis.

Objectives: To answer the PICO(S) question: Is there a difference in clinical longevity between direct and indirect resin composite restorations placed on permanent posterior teeth? Data: Randomized controlled clinical trials (RCTs) investigating direct and indirect resin composite restorations in posterior permanent teeth were considered. Sources: Several electronic databases were searched, with no language or date restrictions. The revised Cochrane Collaboration’s tool for assessing risk of bias (RoB-2) was used to analyze the studies; meta-analyses were run and the certainty of evidence was assessed by the GRADE tool. A subgroup meta-analysis was performed for resin composite restorations placed on posterior worn dentition. Study selection: Twenty-three articles were included in qualitative synthesis, while 8 studies were used for meta- analyses. According to the RoB-2 tool, 5 studies were ranked as “low risk”, 7 had “some concerns”, while 11 papers were rated as “high risk” of bias. There were no statistically significant differences in short-term (p = 0.27; RR=1.54, 95% CI [0.72, 3.33]), medium-term (p = 0.27; RR=1.87, 95% CI [0.61, 5.72]) and long-term longevity (p = 0.86; RR=0.95, 95% CI [0.57, 1.59]). The choice of restorative technique had no influence on short-term survival of resin composite restorations placed on worn dentition (p = 0.13; RR=0.46, 95% CI [0.17, 1.25]). The certainty of evidence was rated as “very low”. Conclusions: Direct and indirect resin composite restorations may show similar clinical longevity in posterior region, regardless of the observation period or substrate (wear-affected and non-affected dentition). The very low quality of evidence suggests that more long-term RCTs are needed to confirm our results

Costs and barriers faced by households seeking malaria treatment in the Upper River Region, The Gambia

Background: Malaria transmission in The Gambia decreased substantially over the last 20 years thanks to the scale-up of control interventions. However, malaria prevalence is still relatively high in eastern Gambia and represents both a health and a financial burden for households. This study aims to quantify the out-of-pocket costs and productivity losses of seeking malaria treatment at household level.Methods: A household survey was carried out through in-person interviews. Respondents were asked about malaria prevention methods, their treatment-seeking behaviour, and any costs incurred for transport, services, food, and/or overnight stays. A bottom-up costing approach was used to calculate the unit cost of treatment and a tobit regression approach to investigate cost drivers.Results: The survey included 864 respondents, mainly subsistence farmers. Most respondents (87%) considered malaria to be a problem affecting their ability to perform their regular duties. Respondents preferred going to a health facility for treatment. The primary reason for not going was related to costs; 70% of respondents incurred costs for seeking health care, with a median of £3.62 (IQR: £1.73 to £6.10). The primary driver of cost was living in one of the villages that are off the main road and/or far from health facilities. 66% reported productivity loss of 5 working days on average during a malaria episode of them or their child.Conclusions: Although malaria prevalence is decreasing and treatment is provided free of charge, households seeking treatment are confronted with out-of-pocket expenditures and lost working days; particularly in remote villages

Control of Bemisia tabaci by entomopathogenic fungi isolated from arid soils in Argentina

Entomopathogenic Hypocreales were isolated from arid soils in Argentina using Tenebrio molitor as bait and tested for their biological performance at 30°C and 45–65% RH. Conidial germination was tested in three vegetable oils (sunflower, olive and maize) at two concentrations (1% and 10%) to evaluate their compatibility for further liquid formulations. According to radial growth and germination results, we selected four isolates to test their pathogenicity against second instar B. tabaci nymphs with the selected oil formulations at 30°C. CEP381 and CEP401 showed the highest radial growth. Isolates CEP381, CEP401, CEP413 and CEP409 (Metarhizium spp.) had similar germination percentages as compared with water control when germinated on either sunflower, olive or maize oils at 10% v/v. The highest mortality of B. tabaci was observed for the isolates CEP381 in sunflower oil and CEP401 in olive oil. Molecular identification of isolates was performed using ITS4–5 primers. All isolates belong to the Metarhizium core group. Tested isolates could grow and infect B. tabaci nymphs at 30°C in some of the vegetable oils as carriers, providing new possibilities for integrated pest management of Bemisia tabaci.Centro de Estudios Parasitológicos y de Vectore

The Impact of Crystal Light Yield Non-Proportionality on a Typical Calorimetric Space Experiment: Beam Test Measurements and Monte Carlo Simulations

Calorimetric space experiments were employed for the direct measurements of cosmic-ray spectra above the TeV region. According to several theoretical models and recent measurements, relevant features in both electron and nucleus fluxes are expected. Unfortunately, sizable disagreements among the current results of different space calorimeters exist. In order to improve the accuracy of future experiments, it is fundamental to understand the reasons of these discrepancies, especially since they are not compatible with the quoted experimental errors. A few articles of different collaborations suggest that a systematic error of a few percentage points related to the energy-scale calibration could explain these differences. In this work, we analyze the impact of the nonproportionality of the light yield of scintillating crystals on the energy scale of typical calorimeters. Space calorimeters are usually calibrated by employing minimal ionizing particles (MIPs), e.g., nonshowering proton or helium nuclei, which feature different ionization density distributions with respect to particles included in showers. By using the experimental data obtained by the CaloCube collaboration and a minimalist model of the light yield as a function of the ionization density, several scintillating crystals (BGO, CsI(Tl), LYSO, YAP, YAG and BaF2) are characterized. Then, the response of a few crystals is implemented inside the Monte Carlo simulation of a space calorimeter to check the energy deposited by electromagnetic and hadronic showers. The results of this work show that the energy scale obtained by MIP calibration could be affected by sizable systematic errors if the nonproportionality of scintillation light is not properly taken into account

Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy

Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma

Mass Drug Administration With High-Dose Ivermectin and Dihydroartemisinin-Piperaquine for Malaria Elimination in an Area of Low Transmission With High Coverage of Malaria Control Interventions: Protocol for the MASSIV Cluster Randomized Clinical Trial

Background: With a decline in malaria burden, innovative interventions and tools are required to reduce malaria transmission further. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) has been identified as a potential tool to further reduce malaria transmission, where coverage of vector control interventions is already high. However, the impact is limited in time. Combining an ACT with an endectocide treatment that is able to reduce vector survival, such as ivermectin (IVM), could increase the impact of MDA and offer a new tool to reduce malaria transmission. Objective: The study objective is to evaluate the impact of MDA with IVM plus dihydroartemisinin-piperaquine (DP) on malaria transmission in an area with high coverage of malaria control interventions. Methods: The study is a cluster randomized trial in the Upper River Region of The Gambia and included 32 villages (16 control and 16 intervention). A buffer zone of ~2 km was created around all intervention clusters. MDA with IVM plus DP was implemented in all intervention villages and the buffer zones; control villages received standard malaria interventions according to the Gambian National Malaria Control Program plans. Results: The MDA campaigns were carried out from August to October 2018 for the first year and from July to September 2019 for the second year. Statistical analysis will commence once the database is completed, cleaned, and locked. Conclusions: This is the first cluster randomized clinical trial of MDA with IVM plus DP. The results will provide evidence on the impact of MDA with IVM plus DP on malaria transmission. Trial Registration: ClinicalTrials.gov NCT03576313; https://clinicaltrials.gov/ct2/show/NCT03576313 International Registered Report Identifier (IRRID): DERR1-10.2196/2090

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor