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Abstract Background This study aims to investigate the association between candidate host genetic polymorphisms and COVID-19 susceptibility, severity, hospitalization, hypoxia, and their combined effect, measured by the polygenic risk score (PRS). Methods Three hundred and seventy-six Lebanese participants, comprising 151 controls and 225 cases, were included. Clinical data were obtained from questionnaires and medical records. DNA isolated from peripheral blood was genotyped for ACE1 rs1799752, ACE2 rs2074192, TMPRSS2 rs75603675 and OAS1 rs107746771 using TaqMan assays, and for TMPRSS2 rs35074065 using Sanger Sequencing. Candidate genetic variants were analyzed in association with COVID-19 susceptibility, severity, hospitalization and hypoxia, using univariate and multivariate models. PRS constructed from the weighted sum of variants was evaluated in association with COVID-19 outcomes. Results In this study, there were no statistically significant differences in the frequencies of candidate variant alleles between cases, controls and within disease outcomes subgroups, after adjustment for confounders. PRS was not associated with COVID-19 susceptibility and hospitalization, it however significantly predicted COVID-19 severity (P = 0.01). Conclusion This study highlights the importance of genetic testing for key host genes involved in COVID-19 life cycle and eventually measuring the PRS which proves to be an important tool for prognosis assessment in vulnerable individuals, potentially enhancing patient care.

Abstract This study presents a method for automating the retrieval of key identifies and links to toxicological data from the Joint FAO/WHO Expert Committee on Food Additives (JECFA) database using web scraping techniques. Although the method primarily serves as an automated indexing tool, facilitating organization and access to relevant reports, monographs, and specifications, it significantly enhances the efficiency of navigating the extensive JECFA database. Researchers can then perform more targeted and efficient searches, although additional manual steps are required to extract and structure the detailed toxicological data. We developed R programming scripts to extract key information, such as chemical names, identifiers, and evaluation reports, from JECFA web pages. The resulting data set comprises 6552 records as of May 2024. We validated the dataset through a systematic comparison with manually collected data, ensuring its reliability. Instructions and code for accessing and processing the dataset, facilitating its reuse in research are provided. The code and dataset are openly available, enabling researchers to efficiently access and analyze toxicological data from the JECFA database.

The aim of this study was to compare animal performance and meat quality of a local cattle breed of Sardinia Island with specialised meat purebred or obtained by crossbreeding. For this purpose, 10 Sardo-Bruna (SB; 5 males, 5 females), 10 Limousine (L; 5 males, 5 females) and 10 Limousine × Sardo-Bruna crossbreed (L × SB; 5 males, 5 females) were compared simultaneously from 12 to 20 ± 1 (mean ± SEM) months old. During the trial, body weight (BW) was recorded once a month for estimating the average daily gain (ADG). At slaughter, carcase measurements, pH and colour traits were recorded from the left side of the carcase. Proximate composition, fatty acid (FA) profile, cooking and drip losses were evaluated using the Longissimus thoracis et lumborum muscle. The SB group showed a lower cold carcase yield compared to L and L × SB genetic types. Males had a higher ADG, slaughter weight, hot and cold carcase weights, hot and cold carcase yields, and cooking losses than females. Females group showed a higher intramuscular fat content and rib fat thickness compared to males. No relevant differences among genetic types and between sexes were observed for meat and fat colours and pH. Concerning the FA profile, SB genetic type evidenced a higher oleic acid content and a better nutritional index than other genetic types while males had a higher PUFA content than females. In conclusion, the results of this study showed that the Limousine breed can be effectively used to enhance carcase yield of local breed without effects on meat quality.

Abstract Corn-based breakfast cereals, known as cornflakes, have become a common breakfast choice worldwide, recognized for their convenience and versatility. However, mycotoxins can contaminate these products, adversely affecting human health. This study assessed the occurrence of major mycotoxins (AFB1, OTA, DON, ZEA, and FUM) in cornflake stock-keeping units (SKUs) marketed in the United Arab Emirates (UAE). It also evaluated the effect of different independent variables (country of origin, temperature on the production day, storage time, presence of chocolate, bran, and nut ingredients) and estimated the exposure levels of the UAE population to these mycotoxins and the associated risk factors. Seventy-six distinct cornflake SKUs were identified through a market screening and tested for mycotoxins using the Enzyme-Linked Immunosorbent Assay (ELISA) technique. AFB1, OTA, ZEA, FUM, and DON were detected in 23.7, 48.7, 27.6, 9.2 and 88.2% of the samples, respectively. The mean concentrations among positive samples were 2.0, 1.0, 10.14, 584.9, and 90.6 μg/kg, respectively. Except for AFB1, the average mycotoxin levels in samples were below the established limits by the European Union (EU). Among positive samples, none exceeded the US FDA limits for all mycotoxins, and only one exceeded the CODEX limit for FUM. On the other hand, four (5.3%), one (1.3%), one (1.3%), and one (1.3%) SKU exceeded EU limits for AFB1, OTA, FUM, and ZEA, respectively. The country of origin (developing vs. developed countries) exhibited a significant effect on AFB1 presence (p

Abstract During summer, ammonia emissions in Southeast Asia influence air pollution and cloud formation. Convective transport by the South Asian monsoon carries these pollutant air masses into the upper troposphere and lower stratosphere (UTLS), where they accumulate under anticyclonic flow conditions. This air mass accumulation is thought to contribute to particle formation and the development of the Asian Tropopause Aerosol Layer (ATAL). Despite the known influence of ammonia and particulate ammonium on air pollution, a comprehensive understanding of the ATAL is lacking. In this modelling study, the influence of ammonia on particle formation is assessed with emphasis on the ATAL. We use the EMAC chemistry-climate model, incorporating new particle formation parameterisations derived from experiments at the CERN CLOUD chamber. Our diurnal cycle analysis confirms that new particle formation mainly occurs during daylight, with a 10-fold enhancement in rate. This increase is prominent in the South Asian monsoon UTLS, where deep convection introduces high ammonia levels from the boundary layer, compared to a baseline scenario without ammonia. Our model simulations reveal that this ammonia-driven particle formation and growth contributes to an increase of up to 80% in cloud condensation nuclei (CCN) concentrations at cloud-forming heights in the South Asian monsoon region. We find that ammonia profoundly influences the aerosol mass and composition in the ATAL through particle growth, as indicated by an order of magnitude increase in nitrate levels linked to ammonia emissions. However, the effect of ammonia-driven new particle formation on aerosol mass in the ATAL is relatively small. Ammonia emissions enhance the regional aerosol optical depth (AOD) for shortwave solar radiation by up to 70%. We conclude that ammonia has a pronounced effect on the ATAL development, composition, the regional AOD, and CCN concentrations.

This study aimed to assess volatile impurities and ethanol content in ethanol-based hand sanitizers. A total of 31 different brands of hand sanitizers were analyzed using headspace gas chromatography-mass spectrometry to detect impurities and determine alcohol content for compliance. Volatile impurities were identified through Mass Spectrometry database analysis, and regression analysis was employed to ascertain ethanol percentage. Furthermore, a simulated toxicological analysis was conducted to evaluate the potential toxic effects associated with hand sanitizer usage.The detected impurities primarily included ethyl acetate, benzene, acetone, and acetal, along with contaminations such as isobutanol and non-recommended alcohols. In addition, 71 % of samples contained less than the recommended 60 % v/v alcohol concentration, failing to comply with guidelines from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). Additionally, the simulation study underscored acute and chronic toxicities primarily linked to benzene contamination.Given that some of the studied products are imported while others are locally produced, it is imperative for consumers worldwide to be informed that certain hand sanitizers may not only be ineffective but also contain harmful residues.

BackgroundAntiseizure medications (ASM) exhibit considerable interindividual variability in terms of efficacy and adverse events. Genetic variation is thought to contribute to these differences in clinical outcomes. Specifically, the response to valproic acid (VPA), a widely used ASM, is influenced by multiple pharmacogenetic factors. However, and in contrast to other ASMs such as phenytoin and carbamazepine, there is a paucity of data on the association between VPA and various gene variants. The aim of this study was hence to evaluate the influence of candidate pharmacogenetic variants on VPA efficacy, toxicity and serum concentrations in a homogeneous cohort of patients newly diagnosed with genetic generalized epilepsies (GGE).MethodsIn this prospective cohort study, demographic, clinical and treatment outcomes of GGE patients were retrieved from their medical records. Whole exome sequencing was performed in collaboration with Epi25. Gene variants associated with VPA efficacy, metabolism and toxicities were retrieved from PharmGKB. An analysis was then conducted to explore potential associations between these gene variants and VPA clinical outcomes.ResultsOf the 166 patients included, 60 (36.1%) experienced treatment failure while 106 (63.9%) achieved treatment success. After adjusting for VPA maintenance dose, carriers of the rs3892097 (CYP2D6) variant were 2.5 times more likely to experience treatment failure compared to wildtype (p = 0.026). The rs1057910 variant (CYP2C9*3) was associated with increased serum VPA concentrations (p = 0.034). Moreover, the rs1137101 variant (LEPR gene, a metabolism regulator) was significantly associated with a higher risk of weight gain (regression coefficient of 3.430 [0.674; 6.186], p = 0.015) and a higher frequency of hair loss (OR = 3.394 [1.157; 9.956], p = 0.026), while the rs4480 variant (SOD2 gene, encoding for a mitochondrial scavenging enzyme) was correlated with a lower frequency of hair loss (OR = 0.276 [0.089; 0.858], p = 0.026).ConclusionThese findings highlight the role of genetic factors in VPA treatment and underscore the potential for developing therapeutic strategies to enhance patient outcomes and minimize adverse effects.

Objectives: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease with systemic manifestations. Heart failure (HF) is the most critical heart condition associated with COPD. Lung diseases are probably associated with right ventricular (RV) dysfunction, but few studies have investigated this. In this study, we identified whether the prevalence of RV dysfunction among patients with COPD is higher than that among patients without COPD. Materials and Methods: In this retrospective cross-sectional study, we included active/former smokers over the age of 40 years with pulmonary function testing (PFT) at the American University of Beirut Medical Center from January to December 2014 and echocardiography within 1 year of the PFT. We classified a total of 135 patients into two groups: a COPD group and a non-COPD control group. Results: COPD was significantly associated with increased odds of increased pulmonary vascular resistance (adjusted odds ratio: 1.99, 95% confidence interval: 1.15-3.46), after adjusting for age, gender, smoking, HF, and diastolic dysfunction. However, COPD was not associated with tricuspid annular plane systolic excursion (p=0.15). Conclusion: Echocardiographic RV dysfunction is associated with COPD. Future prospective research can help put things into perspective and help differentiate COPD severity and projection.

This study investigated the low contact resistivity and Schottky barrier characteristics in p-GaN by modifying the thickness and doping levels of a p-InGaN cap layer. A comparative analysis with highly doped p-InGaN revealed the key mechanisms contributing to low-resistance contacts. Atomic force microscopy inspections showed that the surface roughness depends on the doping levels and cap layer thickness, with higher doping improving the surface quality. Notably, increasing the doping concentration in the p++-InGaN cap layer significantly reduced the specific contact resistivity to 6.4 ± 0.8 × 10−6 Ω·cm2, primarily through enhanced tunneling. Current–voltage (I–V) characteristics indicated that the cap layer’s surface properties and strain-induced polarization effects influenced the Schottky barrier height and reverse current. The reduction in barrier height by approximately 0.42 eV in the p++-InGaN layer enhanced hole tunneling, further lowering the contact resistivity. Additionally, polarization-induced free charges at the metal–semiconductor interface reduced band bending, thereby enhancing carrier transport. A transition in current conduction mechanisms was also observed, shifting from recombination tunneling to space-charge-limited conduction across different voltage ranges. This research underscores the importance of doping, cap layer thickness, and polarization effects in achieving ultra-low contact resistivity, offering valuable insights for improving the performance of p-GaN-based power devices.

Background: Influenza represents a significant global health burden for individuals and society. This study assessed the burden of medically attended influenza at a tertiary medical center in Lebanon to describe the demographics, risk factors, and outcomes prior to the COVID-19 pandemic. Methods: This was a retrospective review of patients who tested positive for the influenza virus during three seasons between July 1, 2016 to June 30, 2019, at the American University of Beirut Medical Center. Results: A total of 2049 patients who tested positive for influenza were analyzed. Influenza A accounted for 79.6 % of cases, and influenza B for 19.7 %, with influenza activity starting in October/November and peaking in December/January. Older age above 65 years (AOR=3.584), obesity (AOR=2.183), and chronic conditions such as chronic lung diseases (AOR=1.832), and bacterial co-infection (AOR= 2.834) were found to be independent risk factors for developing complications. Viral co-infection increased the likelihood of death tenfold. Vaccinated patients had a shorter mean hospital stay duration and a lower intensive care unit admission rate. Conclusion: The burden of medically attended influenza at our tertiary medical center in Lebanon prior to the COVID-19 pandemic was high. Vaccination decreased the likelihood of complications leading to intensive care unit admission in patients at risk.

Background: Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a). We hypothesized that oral delivery of CNP-miR146a would reduce colonic inflammation in a mouse model of established, chronic, T cell-mediated colitis. Methods: The stability of CNP-miR146a and mucosal delivery was assessed in vitro with simulated gastrointestinal fluid and in vivo after oral gavage by quantitative real-time RT-PCR. The efficacy of orally administered CNP-miR146a was tested in mice with established colitis using the model of adoptive naïve T-cell transfer in recombinant activating gene 2 knockout (Rag2−/−) mice. Measured outcomes included histopathology; CD45+ immune cell infiltration; oxidative DNA damage (tissue 8-hydroxy-2′-deoxyguanosine; 8-OHdG); expression of IL-6 and TNF mRNA and protein, and flow cytometry analysis of lamina propria Th1 and Th17 cell populations. Results: miR146a expression remained stable in simulated gastric and intestinal conditions. miR146a expression increased in the intestines of mice six hours following oral gavage of CNP-miR146a. Oral delivery of CNP-miR146a in mice with colitis was associated with reduced inflammation and oxidative stress in the proximal and distal colons as evidenced by histopathology scoring, reduced immune cell infiltration, reduced IL-6 and TNF expression, and decreased populations of CD4+Tbet+IFNg+ Th1, CD4+RorgT+IL17+ Th17, as well as pathogenic double positive IFNg+IL17+ T cells. Conclusions: CNP-miR146a represents a novel orally available therapeutic with high potential to advance into clinical trials.

The pyridinium phenolate punicine is a switchable molecule from Punica granatum. Depending on the pH, punicine exists as a cation, neutral molecule, anion, or dianion. In addition, punicine reacts to light, under the influence of which it forms radical species. We report on three punicine derivatives that possess an adamantyl, 2-methylnonyl, or heptadecyl substituent and on their performance in the flotation of lithium aluminate, an engineered artificial mineral (EnAM) for the recycling of lithium, e.g., from lithium-ion batteries. By optimizing the parameters: pH and light conditions (daylight, darkness), recovery rates of 92% of LiAlO2 are achieved. In all cases, the flotation of the gangue material gehlenite (Ca2Al[AlSiO7]) is suppressed. IR, the contact angle, zeta potential measurements, TG-MS, and PXRD confirm that the punicines interact with the surface of LiAlO2, which is covered by LiAl2(OH)7 after contact to water, resulting in a hydrophobization of the particle. The plasma pretreatment of the lithium aluminate has a significant influence on the flotation results and increases the recovery rates of lithium aluminate in blank tests by 58%. The oxidative plasma leads to a partial dehydratisation of the LiAl2(OH)7 and thus to a hydrophobization of the particles, while a reductive plasma causes a more hydrophilic particle surface.

This study explored how experienced faculty are using social media to support student learning. It analyzed the types of social media learning activities (SMLAs), their design, the cognitive processes that they support, and the types of knowledge that students engage in when completing SMLAs. Data gathered from five different cases of six faculty using social media in their courses revealed that social media has the potential to support student learning and promote different levels of cognitive processes and types of knowledge. Results also revealed that experienced faculty select social media tools based on their technology features or their popularity in the field of study, and they recommend integrating several media sources in the design of a single SMLA. Furthermore, this study suggested that experienced faculty who use social media, specifically wikis and blogs, use them as Learning Management Systems (LMS). Finally, the social factor of social media was not evident in the design of the learning activities, and faculty reported promoting more dialogue in their revised SMLA. The findings of this study yielded significant considerations for faculty when designing SMLA.

Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzymopathies in humans, present in approximately half a billion people worldwide. More than 230 clinically relevant G6PD mutations of different classes have been reported to date. We hereby describe a patient with chronic hemolysis who presents a substitution of arginine by glycine at position 219 in G6PD protein. The variant was never described in an original publication or characterized on a molecular level. In the present study, we provide structural and biochemical evidence for the molecular basis of its pathogenicity. When compared to the wild-type enzyme, the Arg219Gly mutation markedly reduces the catalytic activity by 50-fold while having a negligible effect on substrate binding affinity. The mutation preserves secondary protein structure, but greatly decreases stability at higher temperatures and to trypsin digestion. Size exclusion chromatography elution profiles show monomeric and dimeric forms for the mutant, but only the latter for the wild-type form, suggesting a critical role of arginine 219 in G6PD dimer formation. Our findings have implications in the development of small molecule activators, with the goal of rescuing the phenotype observed in this and possibly other related mutants.

This work proposes a holistic quantitative snow avalanche risk assessment that evaluates, at reasonable computational costs and for various types of buildings, the impact of forest cover changes on the probability distribution of runout distances, impact pressures and subsequent risk estimates. A typical case study of the French Alps shows that, from a completely deforested to a completely forested path, avalanche risk for a building located downslope decreases by 53–99%, depending on how forest cover is accounted for in avalanche statistical–dynamical modeling. Local forest cover data inferred from old maps and photographs further demonstrates that a 20–60% risk reduction actually occurred between 1825 and 2017 at the site because of the afforestation dynamics, with significant modulations according to the considered building technology. These results (1) assert the protective role of forests against snow avalanches, (2) highlight the potential of combining nature-based solutions with traditional structural measures to reduce risk to acceptable levels at reasonable costs, (3) suggest a significant decrease in risk to settlements in areas that encountered similar forest cover changes and (4) open the door to the quantification of long-term avalanche risk changes as a function of changes of all its hazard, vulnerability and exposure drivers in various mountain context.

Abstract Nephrocalcinosis is a complex disease with a multitude of triggering factors. An association with congenital hypothyroidism has been described in the literature, but the mechanisms leading to its development remain unclear. A 7‐month‐old infant presented with muscular hypotonia and signs of malnutrition was diagnosed with congenital hypothyroidism, nephrocalcinosis of unclear origin, and multiple kidney stones. Urine analysis revealed the presence of calcium oxalate crystals and slightly elevated oxaluria without hypercalciuria. Targeted exome sequencing found no variants in the four causative genes of primary oxaluria, namely AGXT, CBX5, GRHPR, and HOGA1. The clinical outcome was favorable with thyroid hormone and potassium citrate treatment. Ultrasound follow‐up showed progressive improvement of nephrocalcinosis. The low level of urinary oxalate and the prevalence of dihydrate calcium oxalate crystals spoke against primary or secondary oxaluria. Recent evidence from mitochondrial research shows that thyroid hormone T3 enhances mitochondrial calcium levels by stimulating calcium uptake by the mitochondrial calcium uniporter. A reduced calcium uptake and metabolism in mitochondria might represent an explanation for cytoplasmic calcium accumulation in tubular cells, subsequently precipitating nephrocalcinosis in the absence of thyroid hormone. Even if the pathophysiological mechanisms are not yet fully understood, recent evidence is supportive of a causal relationship between hypothyroidism and nephrocalcinosis, a sometimes overlooked association.

The anticancer efficacy of Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate internalized through a sortilin-mediated process, was assessed in a triple-negative breast cancer-derived MDA-MB-231 immunocompromised xenograft tumor model where complete tumor regression was observed for more than 40 days after the last treatment. Surprisingly, immunohistochemistry analysis revealed high staining of STING, a master regulator in the cancer-immunity cycle. A weekly administration of TH1902 as a single agent in a murine B16-F10 melanoma syngeneic tumor model demonstrated superior tumor growth inhibition than did docetaxel. A net increase in CD45 leukocyte infiltration within TH1902-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages was observed. Increased staining of perforin, granzyme B, and caspase-3 was suggestive of elevated cytotoxic T and natural killer cell activities. Combined TH1902/anti-PD-L1 treatment led to increases in tumor growth inhibition and median animal survival. TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.

BackgroundOvarian Cancer (OC) stands as the most lethal gynecological malignancy, presenting an urgent clinical challenge in the quest to improve response rates. One approach to address this challenge is through drug repurposing, exemplified by the investigation of metabolic-modulating drugs such as Metformin (MTF) and Simvastatin (SIM). This study aims to explore the molecular mechanisms contributing to the potential synergistic anti-cancer effects between MTF and SIM on ovarian cancer cells.MethodsWe assessed the effects of the combination on the proliferation and viability of two cell lines OVCAR-3 and SKOV-3. IC50 concentrations of MTF and SIM were determined using a proliferation assay, followed by subtoxic concentrations to explore the potential synergistic effects on the viability of both cell lines. Transcriptomic analysis was conducted on OVCAR-3 treated cells, and the findings were validated by assessing the expression levels of differentially expressed genes (DEGs) through real-time PCR in both cell lines SK-OV-3 and OVCAR-3.ResultsCytotoxicity analysis guided the selection of treatment concentrations as such MTF 10 mM and SIM 5 μM. The combined treatment of MTF and SIM demonstrated a synergistic inhibition of proliferation and viability in both cell lines. In OVCAR-3, exclusive identification of 507 DEGs was seen in the combination arm. Upregulation of FOXO3, RhoA, and TNFα, along with downregulation of PIK3R1, SKP2, and ATP6V1D levels, was observed in OVCAR-3 treated cells. Real-time PCR validation confirmed the consistency of expression levels for the mentioned DEGs.ConclusionOur data strongly supports the presence of synergy between MTF and SIM in OC cells. The combination's effect is associated with the dysregulation of genes in the key regulators AMPK and mTOR alongside other interconnected pathways.

Background. Rates of major bleeding and intraprocedural thrombotic events (IPTE) in the setting of percutaneous coronary intervention (PCI) using weight-adjusted unfractionated heparin (UFH) without activated clotting time (ACT) monitoring are not known. Methods. We reviewed 2,748 consecutive patients who underwent coronary angiography at our tertiary care university hospital between January 2017 and December 2020. All patients who underwent PCI with weight-adjusted UFH without ACT guidance were considered for further analysis. Major bleeding complications occurring within 48 hours of PCI were collected from patients’ medical records. IPTE were collected independently by two interventional cardiologists after review of coronary angiograms. Results. There were 718 patients included in the analysis (65.4 ± 12.2 years old; 81.3% male). In total, 45 patients (7.8%) experienced a major bleed or IPTE. The most common IPTE were slow/no reflow (1.5%) and coronary artery dissection with decreased flow (1.1%). Other IPTE occurred in

Background. Colchicine has shown potential cardioprotective effects owing to its broad anti-inflammatory properties. We performed a meta-analysis to assess its safety and efficacy in secondary prevention in patients with established coronary artery disease (CAD). Methods. We searched Ovid Healthstar, MEDLINE, and Embase (inception to May 2022) for randomized controlled trials (RCTs) evaluating the cardiovascular effects of colchicine compared with placebo or usual care in patients with CAD. Study-level data on efficacy and safety outcomes were pooled using the Peto method. The primary outcome was the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Results. A total of 8 RCTs were included with a follow-up duration of ≥1 month, comprising a total of 12,151 patients. Compared with placebo or usual care, colchicine was associated with a significant risk reduction in the primary outcome (odds ratio (OR) 0.70, 95% CI 0.60 to 0.83, P