Methodological Issues with Head and Neck Cancer Prognostic Risk Prediction Models.

OBJECTIVE: Prognostic risk prediction models estimate the probability of developing head and neck cancer (HNC), providing valuable information for managing the disease. While different prognostic HNC risk prediction models have been developed worldwide, a comprehensive evaluation of their methods is lacking. We conducted a scoping review with a critical assessment aiming to identify the methodological strengths and limitations of HNC risk prediction models. METHOD: We searched Medline, Embase, Scopus, Web of Science, and CAB Abstracts databases and included full-text-available peer-reviewed published papers on developing or validating a prognostic HNC risk prediction model. Study quality was appraised using the PROBAST tool. RESULTS: Nine papers were included. Although all had a high risk of bias, mainly in the analysis domain, only two studies had high concerns about clinical applicability. CONCLUSION: Currently published studies provide insufficient information on methods, making it difficult to judge the models' quality and applicability. Future investigations should follow the guidelines in reporting the prediction modelling studies.

Contributions of the international plant science community to the fight against infectious diseases in humans-part 2: Affordable drugs in edible plants for endemic and re-emerging diseases.

The fight against infectious diseases often focuses on epidemics and pandemics, which demand urgent resources and command attention from the health authorities and media. However, the vast majority of deaths caused by infectious diseases occur in endemic zones, particularly in developing countries, placing a disproportionate burden on underfunded health systems and often requiring international interventions. The provision of vaccines and other biologics is hampered not only by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, but also by challenges caused by distribution and storage, particularly in regions without a complete cold chain. In this review article, we consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves of Artemisia annua against malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures. Recent FDA approval of the first orally delivered protein drug encapsulated in plant cells to treat peanut allergy has opened the door for the development of affordable oral drugs that can be manufactured and distributed in remote areas without cold storage infrastructure and that eliminate the need for expensive purification steps and sterile delivery by injection.

Contributions of the international plant science community to the fight against human infectious diseases - part 1: epidemic and pandemic diseases.

Infectious diseases, also known as transmissible or communicable diseases, are caused by pathogens or parasites that spread in communities by direct contact with infected individuals or contaminated materials, through droplets and aerosols, or via vectors such as insects. Such diseases cause ˜17% of all human deaths and their management and control places an immense burden on healthcare systems worldwide. Traditional approaches for the prevention and control of infectious diseases include vaccination programmes, hygiene measures and drugs that suppress the pathogen, treat the disease symptoms or attenuate aggressive reactions of the host immune system. The provision of vaccines and biologic drugs such as antibodies is hampered by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, particularly in developing countries where infectious diseases are prevalent and poorly controlled. Molecular farming, which uses plants for protein expression, is a promising strategy to address the drawbacks of current manufacturing platforms. In this review article, we consider the potential of molecular farming to address healthcare demands for the most prevalent and important epidemic and pandemic diseases, focussing on recent outbreaks of high-mortality coronavirus infections and diseases that disproportionately affect the developing world.

Quantitative Bias Analysis of misclassification in case-control studies: an example with Human Papillomavirus and Oropharyngeal Cancer.

OBJECTIVE: Laprise et al. (2019) observed a positive association between oral sex practices and oropharyngeal cancers (OPC) among HPV-negative individuals. Because oral HPV infections are likely to be transmitted through oral sex, these results are counterintuitive. We revisit Laprise et. al's analysis with the objective of estimating the impact of misclassification of HPV infection on the association between oral sex practices and OPC. METHODS: Data were drawn from the Head and Neck Cancer (HeNCe) Life study, a hospital-based case control study of head and neck cancer with frequency-matched controls by age and sex from 4 major referral hospitals in Montreal, Canada. We included only OPC cases (n = 188) and controls (n = 429) and used predictive value weighting, under differential and non-differential scenarios, to evaluate the misclassification. Subsequently, we used logistic regression and 95% confidence intervals to estimate the association between oral sex practice and OPC among HPV-negative individuals. RESULTS: Our results showed that the previously reported association between oral sex practices and OPC among HPV-negative individuals was attenuated or nullified both under differential and non-differential scenarios. CONCLUSION: The association between oral sex practice and OPC could be explained by biases in the data (e.g., HPV mediator misclassification). Our results highlight the need for widespread adoption of Quantitative Bias Analysis in oral health research.

Correction to: Acetylcholinesterase inhibitors and the risk of osteoporotic fractures: nested case-control study.

Please find below the correction for the paragraph under the Heading "Materials and methods - Regulatory approval".

Molecular farming of antimicrobial peptides: available platforms and strategies for improving protein biosynthesis using modified virus vectors.

The constant demand for new antibiotic drugs has driven efforts by the scientific community to prospect for peptides with a broad spectrum of action. In this context, antimicrobial peptides (AMPs) have acquired great scientific importance in recent years due to their ability to possess antimicrobial and immunomodulatory activity. In the last two decades, plants have attracted the interest of the scientific community and industry as regards their potential as biofactories of heterologous proteins. One of the most promising approaches is the use of viral vectors to maximize the transient expression of drugs in the leaves of the plant Nicotiana benthamiana. Recently, the MagnifectionTM expression system was launched. This sophisticated commercial platform allows the assembly of the viral particle in leaf cells and the systemic spread of heterologous protein biosynthesis in green tissues caused by Agrobacterium tumefaciens "gene delivery method". The system also presents increased gene expression levels mediated by potent viral expression machinery. These characteristics allow the mass recovery of heterologous proteins in the leaves of N. benthamiana in 8 to 10 days. This system was highly efficient for the synthesis of different classes of pharmacological proteins and contains enormous potential for the rapid and abundant biosynthesis of AMPs.

A qualitative study on the oral health of humanitarian migrants in Canada.

OBJECTIVES: There is limited evidence to guide oral health policy and services for the 25,000 refugees and asylum seekers who arrive in Canada yearly. The purpose of this study was to explore and understand the pre-migration use of dental services, oral health knowledge, and the effects of oral disease among newly arrived humanitarian migrants in order to inform policy and practice for the population. METHODS: Using focused ethnography and the public health model of the dental care process, we conducted face-to-face interviews (50-60 minutes) with a purposive sample of humanitarian migrants who had indicated the need for dental care. We observed mobile dental clinics that provided care to underserved communities in Montreal. Data were analyzed using a thematic and contextual approach that combined inductive and deductive frameworks. RESULTS: Participants included 25 humanitarian migrants from four global geographical regions. Five major thematic categories were explored: problem-based dental consultation, self-assessed oral health status, causes of oral diseases, personal oral hygiene, and good oral health for wellbeing. In their countries of origin, participants consulted a dentist when oral symptoms persisted. They cited excessive sugar consumption and inadequate oral hygiene as causes of oral diseases, and reported significant oral diseases impacts that limited their daily functions and wellbeing once in Canada. CONCLUSIONS: Humanitarian migrants were knowledgeable about causes of oral disease and the importance of good oral health, yet poor oral health continued to affect their lives in Canada in important ways.

Acetylcholinesterase inhibitors and the risk of osteoporotic fractures: nested case-control study.

The objective of this study was to analyze the effect of acetylcholinesterase inhibitors (AChEIs) on the risk of osteoporotic fractures in Alzheimer patients. A nested case-control study was conducted on 1190 cases and 4760 controls. The use of AChEIs was found to decrease the risk of osteoporotic fractures in these patients. INTRODUCTION: The objective of this study is to estimate the extent to which the use of AChEIs is associated with a reduction in the risk of osteoporotic fractures. METHODS: A nested case-control study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) database (1998-2013). The study cohort consisted of Alzheimer's Disease (AD) patients aged ≥ 65 years with no previous history of osteoporotic fractures at cohort baseline. Cases were individuals who suffered an osteoporotic fracture during the study period, whereas controls were subject who did not experience any osteoporotic fractures during the same period. Controls were drawn from the population time at risk while being matched to the cases in respect to age, sex, up-to-standard follow-up in the CPRD, calendar time, and duration of AD (control-to-case ratio: 4-to-1). Information on the use of AChEIs and the relevant potential confounders was ascertained from the CPRD database for all the cases and controls. RESULTS: We identified 1190 cases and 4760 controls. Compared to non-users, any use of AChEIs prior to the fracture was associated with a reduction in the fracture risk [adjusted odds ratio (OR) 0.80 (confidence interval (CI) 95%, 0.70-0.91)]. The use of AChEIs corresponding to a proportion of days covered of 0.8-1.0 was associated with a lower osteoporotic fracture risk compared to non-use [adjusted OR 0.76 (CI 95%, 0.66-0.87)]. CONCLUSIONS: In this study using large primary care databases, the use and treatment adherence to AChEIs were associated with a decreased risk of osteoporotic fractures in elderly AD patients.

Association between metabolic syndrome and gingival inflammation in obese children.

BACKGROUND AND OBJECTIVE: Our previous work showed a positive association between metabolic syndrome (MetS) and gingival crevicular fluid (GCF) tumour necrosis factor-alpha (TNF-α) in a sample of obese and non-obese children. However, whether this association persists among obese children is unknown. We aim to investigate the extent to which MetS is associated with GCF TNF-α level among obese children. METHODOLOGY: We performed a cross-sectional analysis using data from visit 1 of the QUebec Adipose and Lifestyle InvesTigation in Youth cohort. A total of 219 obese children aged 8-10 years, for whom data were available for both MetS and TNF-α, were included in our analysis. The independent variable, MetS, was defined according to the International Diabetes Federation recommendations. GCF samples were collected from the gingival sulcus using a paper strip, and the concentration of TNF-α was determined by enzyme-linked immunosorbent assay. Analyses included descriptive statistics and sex-specific linear regression analyses adjusting for potential confounders. RESULTS: In this sample comprising only obese children, 24 (10.9%) had MetS. Among obese boys, those with MetS had 44.9% higher GCF TNF-α (95% confidence interval: 16.5%-73.3%) compared to those without MetS. No such association was detected in obese girls. CONCLUSION: MetS was positively associated with GCF TNF-α concentration in obese boys. These results suggest that obese boys with MetS may have a worse gingival health profile compared to their obese counterpart without MetS.

Effect of acetylcholinesterase inhibitors on post-surgical complications and mortality following a hip fracture: a cohort study.

There is increasing evidence suggesting that the use of acetylcholinesterase inhibitors may have beneficial effects on bone. Data on the potential post-surgical effects of these medications on orthopedic interventions are very limited. This study was designed to determine whether the use of acetylcholinesterase inhibitors is associated with a decrease in post-surgical mortality and complications in hip fracture patients with Alzheimer's disease. To accomplish this objective, a retrospective cohort study was performed using data from the Clinical Practice Research Database, UK. The study included 532 Alzheimer's disease patients of age 65 years and older, who sustained a hip fracture between 1998 and 2012. During the follow-up period, 34% of the patients died (n=182), 22% sustained a second hip fracture (n=118) and 5% (n=29) required reintervention. The users of acetylcholinesterase inhibitors had a 56% reduction in all-cause mortality (HR= 0.44, 95% CI 0.30-0.63) and a 41% reduction in second hip fracture incidence during a year of post-surgical follow-up (HR= 0.59, 95% CI 0.38-0.94) after adjusting for potential confounders. Our results show that acetylcholinesterase inhibitors may have the potential to reduce all-cause mortality and the risk of suffering a second hip fracture during the first year after surgery.

Investigating Socioeconomic Position in Dental Caries and Traumatic Dental Injury among Children in Quebec.

OBJECTIVES: Socioeconomic position (SEP) is inversely associated with most oral health outcomes, but the patterns of association may vary depending on the specific outcome. We estimated associations between SEP and two oral health outcomes, dental caries and traumatic dental injuries (TDI), in Quebec children. METHODS: We used data from the baseline visit of the QUALITY (QUebec Adipose and Lifestyle Investigation in Youth) Cohort, an ongoing study in Montreal and Quebec, Canada. The analytical sample included 590 children aged 8-10 years. Data on parents' SEP (household income, education) and children's health behaviours and involvement in sports were obtained through questionnaires and interviews. Oral health outcomes (dental caries and TDI in permanent teeth) were assessed by clinical oral exam. Negative binomial regression was used to model dental caries (DMFS index) and number of teeth with TDI adjusting for selected covariates. RESULTS: The mean (SD) DMFS and number of TDI were 0.61 (1.43) and 0.12 (0.43), respectively. Compared to the upper quartile of income, children in the lower quartile had a DMFS approximately 3 times higher (PRR=2.68, 95% CI: 1.43, 5.04). Adjusting for oral health and nutritional behaviours had no effect. Conversely, children in the highest income quartile had a 3 times higher number of teeth with TDI compared to the lowest quartile (PRR=3.14, 95% CI: 1.22, 8.08). Physical activity did not explain this relationship. Parents' education was not associated with dental caries or TDI. CONCLUSION: SEP seems to play a different role in the cause of dental caries and TDI.

Engineering soya bean seeds as a scalable platform to produce cyanovirin-N, a non-ARV microbicide against HIV.

There is an urgent need to provide effective anti-HIV microbicides to resource-poor areas worldwide. Some of the most promising microbicide candidates are biotherapeutics targeting viral entry. To provide biotherapeutics to poorer areas, it is vital to reduce the cost. Here, we report the production of biologically active recombinant cyanovirin-N (rCV-N), an antiviral protein, in genetically engineered soya bean seeds. Pure, biologically active rCV-N was isolated with a yield of 350 µg/g of dry seed weight. The observed amino acid sequence of rCV-N matched the expected sequence of native CV-N, as did the mass of rCV-N (11 009 Da). Purified rCV-N from soya is active in anti-HIV assays with an EC50 of 0.82-2.7 nM (compared to 0.45-1.8 nM for E. coli-produced CV-N). Standard industrial processing of soya bean seeds to harvest soya bean oil does not diminish the antiviral activity of recovered rCV-N, allowing the use of industrial soya bean processing to generate both soya bean oil and a recombinant protein for anti-HIV microbicide development.

Mass spectrometry characterisation of fatty acids from metabolically engineered soybean seeds.

Improving the quality and performance of soybean oil as biodiesel depends on the chemical composition of its fatty acids and requires an increase in monounsaturated acids and a reduction in polyunsaturated acids. Despite its current use as a source of biofuel, soybean oil contains an average of 25 % oleic acid and 13 % palmitic acid, which negatively impacts its oxidative stability and freezing point, causing a high rate of nitrogen oxide emission. Gas chromatography and ion mobility mass spectrometry were conducted on soybean fatty acids from metabolically engineered seed extracts to determine the nature of the structural oleic and palmitic acids. The soybean genes FAD2-1 and FatB were placed under the control of the 35SCaMV constitutive promoter, introduced to soybean embryonic axes by particle bombardment and down-regulated using RNA interference technology. Results indicate that the metabolically engineered plants exhibited a significant increase in oleic acid (up to 94.58 %) and a reduction in palmitic acid (to <3 %) in their seed oil content. No structural differences were observed between the fatty acids of the transgenic and non-transgenic oil extracts.

A Cluster Analysis of Oral and Cognitive Health Indicators: An Exploratory Study on Cholinergic Activity as the Link.

INTRODUCTION: Poor oral health has been suggested as a risk factor for cognitive decline. Yet, biologically plausible mechanisms explaining this relationship remain unknown. OBJECTIVES: We aimed (1) to identify oral and cognitive health clustering patterns among middle-aged to elderly Canadians and (2) to investigate the extent to which these patterns could be explained by bone mineral density (BMD), a proxy measure of the cholinergic neurons' activity. METHODS: This cross-sectional study used baseline data from the Comprehensive cohort of the Canadian Longitudinal Study of Aging (CLSA). Oral health was assessed by a self-report questionnaire, and 7 task-based instruments measured cognitive health. We identified oral and cognitive health clusters, our outcome variables, using latent class analysis. Two sets of multivariate logistic regression and 95% confidence intervals were used to investigate whether BMD explains the odds of membership in a certain oral and cognitive health group. The final models were adjusted for socioeconomic, health, and lifestyle factors. RESULTS: Our study sample (N = 25,444: 13,035 males, 12,409 females) was grouped into 5 and 4 clusters based on the oral health status and performance on the cognitive tasks, respectively. After adjusting for all potential covariates, increase in BMD was not associated with higher odds of membership in classes with better oral health (odds ratio [OR] = 1.58 [95% confidence interval {CI}: 0.85-2.92]) and cognitive health (OR = 1.61 [95% CI: 1-2.6]) compared with the groups with the least favorable oral and cognitive health status, respectively. CONCLUSION: Middle-aged and elderly Canadians show different oral and cognitive health profiles, based on their denture-wearing status and performance on cognitive tests. No evidence could be found to support BMD in place of cholinergic neurons' activity as the common explanatory factor behind the association between oral health and cognitive health. KNOWLEDGE TRANSFER STATEMENT: This study is probably the first of its kind to shed light on the cholinergic system as a potential pathway influencing oral and cognitive health. Our findings may support the notion that any potential association between poor oral health and cognitive health might be explained by common contributors, helping clinicians to find the common risk factors for both conditions.

Epigenome-Driven Strategies for Personalized Cancer Immunotherapy.

Fighting cancer remains one of the greatest challenges for science in the 21st century. Advances in immunotherapy against different types of cancer have greatly contributed to the treatment, remission, and cure of patients. In this context, knowledge of epigenetic phenomena, their relationship with tumor cells and how the immune system can be epigenetically modulated represent some of the greatest advances in the development of anticancer therapies. Epigenetics is a rapidly growing field that studies how environmental factors can affect gene expression without altering DNA sequence. Epigenomic changes include DNA methylation, histone modifications, and non-coding RNA regulation, which impact cellular function. Epigenetics has shown promise in developing cancer therapies, such as immunotherapy, which aims to stimulate the immune system to attack cancer cells. For example, PD-1 and PD-L1 are biomarkers that regulate the immune response to cancer cells and recent studies have shown that epigenetic modifications can affect their expression, potentially influencing the efficacy of immunotherapy. New therapies targeting epigenetic modifications, such as histone deacetylases and DNA methyltransferases, are being developed for cancer treatment, and some have shown promise in preclinical studies and clinical trials. With growing understanding of epigenetic regulation, we can expect more personalized and effective cancer immunotherapies in the future. This review highlights key advances in the use of epigenetic and epigenomic tools and modern immuno-oncology strategies to treat several types of tumors.

Accumulation of functional recombinant human coagulation factor IX in transgenic soybean seeds.

The seed-based production of recombinant proteins is an efficient strategy to achieve the accumulation, correct folding, and increased stability of these recombinant proteins. Among potential plant molecular farming systems, soybean [Glycine max (L.) Merrill] is a viable option for the production of recombinant proteins due to its high protein content, known regulatory sequences, efficient gene transfer protocols, and a scalable production system under greenhouse conditions. We report here the expression and stable accumulation of human coagulation factor IX (hFIX) in transgenic soybean seeds. A biolistic process was utilised to co-introduce a plasmid carrying the hFIX gene under the transcriptional control of the α' subunit of a ß-conglycinin seed-specific promoter and an α-Coixin signal peptide in soybean embryonic axes from mature seeds. The 56-kDa hFIX protein was expressed in the transgenic seeds at levels of up to 0.23% (0.8 g kg(-1) seed) of the total soluble seed protein as determined by an enzyme-linked immunosorbent assay (ELISA) and western blot. Ultrastructural immunocytochemistry assays indicated that the recombinant hFIX in seed cotyledonary cells was efficiently directed to protein storage vacuoles. Mass spectrometry characterisation confirmed the presence of the hFIX recombinant protein sequence. Protein extracts from transgenic seeds showed a blood-clotting activity of up to 1.4% of normal plasma. Our results demonstrate the correct processing and stable accumulation of functional hFIX in soybean seeds stored for 6 years under room temperature conditions (22 ± 2°C).

Expression of functional recombinant human growth hormone in transgenic soybean seeds.

We produced human growth hormone (hGH), a protein that stimulates growth and cell reproduction, in genetically engineered soybean [Glycine max (L.) Merrill] seeds. Utilising the alpha prime (α') subunit of ß-conglycinin tissue-specific promoter from soybean and the α-Coixin signal peptide from Coix lacryma-jobi, we obtained transgenic soybean lines that expressed the mature form of hGH in their seeds. Expression levels of bioactive hGH up to 2.9% of the total soluble seed protein content (corresponding to approximately 9 g kg(-1)) were measured in mature dry soybean seeds. The results of ultrastructural immunocytochemistry assays indicated that the recombinant hGH in seed cotyledonary cells was efficiently directed to protein storage vacuoles. Specific bioassays demonstrated that the hGH expressed in the soybean seeds was fully active. The recombinant hGH protein sequence was confirmed by mass spectrometry characterisation. These results demonstrate that the utilisation of tissue-specific regulatory sequences is an attractive and viable option for achieving high-yield production of recombinant proteins in stable transgenic soybean seeds.

[Physical compatibility of sodium bicarbonate with other drugs often administered in the intensive care unit]. / Compatibilidad física del bicarbonato sódico con fármacos de uso frecuente en la unidad de cuidados intensivos.

INTRODUCTION: Acid-base disorders are associated with many diseases of the critically ill patient. Early treatment with sodium bicarbonate of these metabolic disorders is required for their normalization. This is an alkaline electrolyte solution administered by continuous or intermittent infusion. Its incompatibility due to its alkaline pH has been described, as it produces insoluble carbonate precipitation and causes carbon dioxide gas when mixed with acidic solutions. MATERIAL AND METHOD: An in vitro experimental study was performed. Bicarbonate was mixed with 13 drugs simulating Y-site administration. We combined 5 ml bicarbonate with 5 ml of every drug, at highest daily concentration used. The samples were visually examined to detect color changes, cloudiness, precipitation or gas formation, pH measurement and spectrophotometric analysis at 450 nm and 620 nm. The samples were evaluated at 0, 15, 30, 60 and 120 minutes. The compatibility criteria were absence of visual changes, pH changes<0.5 and variability of absorbance <0.01. RESULTS: We studied each drug individually and mixed with bicarbonate with 27 samples, and 135 measurements were performed. The incompatibilities did not always produce visual changes. Knowing the pH of drugs does not guarantee the compatibility of the mixture. Nitroglycerin with pH 4 is compatible with bicarbonate. Thiopental with pH 11 makes precipitation. Higher absorbances showed color changes, cloudiness and precipitation. CONCLUSIONS: Bicarbonate is physically compatible with esmolol, furosemide, heparin, insulin, morphine, nimodipine, nitroglycerin and urapidil and incompatible with amiodarone, cisatracurium, haloperidol, midazolam and thiopental.

Oral health of Brazilian individuals with mucopolyssaccaridosis.

PURPOSE: This study described and compared the oral characteristics of Brazilian individuals with mucopolysaccharidosis (MPS) and without MPS. METHODS: A cross-sectional study was performed with 29 individuals with MPS and 29 without MPS and their parents/guardians. The individuals were aged between 3 and 21 years and attended at two hospitals in Belo Horizonte, southeastern Brazil. The dental characteristics were evaluated by clinical examination of dental caries, gingivitis, malocclusion, dental anomalies and developmental defects of enamel. The parents/guardians answered a questionnaire about the sociodemographic and behavioural aspects of their children. The study was approved by the Research Ethics Committee of the Federal University of Minas Gerais. RESULTS: The average age of the individuals was 13.9 years (± 7.2). The majority were male (58.6%), had black/brown skin (70.7%) and were from favored economic class (89.7%). Dental caries, gingivitis, malocclusion and dental anomalies were more prevalent in the MPS group (p < 0.05). CONCLUSION: The individuals with MPS had a higher prevalence of oral diseases and dental anomalies than the group without MPS.