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Abstract A research protocol is a document that outlines the proposed research idea and is submitted to funding agencies, institutions, or journals for approval. Writing a research protocol represents a challenge, particularly for early-career researchers. In this guide, we aim to provide detailed guidance with the key components and offer practical tips for crafting a research protocol in line with the various study designs. Specifically, the structure of a research protocol should contain the following items: (1) a title that is specific, catchy, and impressive within the word limitation; (2) an abstract that briefs the critical points of the study; (3) an introduction highlighting the study context from broad to narrow and defining the knowledge gap; (4) a justification underlining the significance of the proposed study; (5) Specific, Measurable, Attainable, Relevant, and Time-bound (SMART) objective(s) and aim(s); (6) a methodology covering seven sub-items, including [i] study design and settings, [ii] study subjects, [iii] sample size calculation and sampling, [iv] participants recruitment and follow-up, [v] questionnaire development, [vi] potential variables and outcomes, and [vii] data analysis plan; (7) dissemination of the results; (8) ethics and conflict of interests; (9) budgets analysis/ funding disclosure; and (10) references. This guide will give an overview of these steps and provide clear and concise tips on how to successfully draft a scientific protocol. With careful planning and appropriate guidance, it is possible to develop a well-structured and compelling protocol to obtain approval for the conduction of the study or funding from agencies, institutions, or organizations.

Abstract Background Cystoisospora felis or Isospora felis is a ubiquitous apicomplexan protozoon parasite infecting domestic cats worldwide. Objectives of the study this study aims to identify the causative agent of diarrhea in cats by determining several elevating stressors caused by these coccidian protozoans with molecular characterization. So, from January 2023 to April 2023, a total of 370 domestic cats were hospitalized at various clinics in the Cairo and Giza Governorates. Fecal samples were taken from these animals and examined by concentration floatation techniques using a saturated salt solution. The positive samples were sporulated to identify the collected oocyst. Venous blood was taken from the infected cats to evaluate the associated oxidative stress marker (lipid peroxidation products (MDA). Results Out of 370 examined domestic cats, 27(7.29%) were positive for C. felis. The MDA levels increased with age, and females were higher than males. DNA was extracted from fecal samples for amplification of the ITS1 gene, followed by sequencing. The ITS1 gene was amplified and showed bands at 224 bp. The partial nucleotide sequence of the ITS1 gene was aligned with the reference sequences. In a conclusion C. felis increases the free radicals, which in turn means the animals have stress and need a schedule to treat these animals with new, safe protocol drugs that give no resistance and are highly efficient.

We examined intraspecific infectious rivalry in a dynamic contagious disease model. A non-linear dynamic model that considers multiple individual categories was used to study the transmission of infectious diseases. The combined effect of parameter sensitivities on the model was simulated using system sensitivities. To investigate the dynamic behavior and complexity of the model, the Caputo-Fabrizio (C-F) fractional derivative was utilized. The behavior of the proposed model around the parameters was examined using sensitivity analysis, and fractional solutions included more information than the classical model. Fixed point theory was used to analyze the existence and uniqueness of the solution. The Ulam-Hyers (U-H) criterion was used to examine the stability of the system. A numerical approach based on the C-F fractional operator was utilized to improve comprehension and treatment of the infectious disease model. A more precise and valuable technique for solving the infectious disease model was used in MATLAB numerical simulations to demonstrate. Time series and phase diagrams with different orders and parameters were generated. We aimed to expedite patient recovery while reducing the frequency of disease transmission in the community.

Abstract One of the most common health concerns disturbing people within working years globally is diabetes mellitus (DM). One well-known consequence of DM is vascular damage, which can manifest as macro- and microangiopathy affecting the ocular retina. Therefore, Diabetic macular edema (DME) is a major sight-threatening complication of diabetic retinopathy (DR) worldwide. It is the most prevalent cause of significant vision impairment in diabetic patients. Long-term vision loss can be avoided by following early DME treatment guidelines in everyday life. Hence, there are various therapeutic approaches for DME management. Currently, the first-line treatment for DME is anti-VEGF family drugs, such as ranibizumab, brolucizumab, bevacizumab, and aflibercept. Nevertheless, relapses of the disease, inadequate response, and resistance during anti-VEGF therapy are still seen because of the intricate pathophysiological foundation of the disease. Consequently, there is an excellent requirement for therapeutic approaches to advance and become better at controlling diseases more satisfactorily and require fewer treatments overall. We conducted a thorough literature search in the current review to present a comprehensive overview of the primary data about the current DME therapeutic agents. We also covered the novel advances in DME management and probable future treatments being investigated and developed. This review recommended that Large clinical trials should afford sufficient evidence to support these innovative treatment modalities.

Multiple myeloma is a hematological malignancy characterized by the clonal proliferation of plasma cells. Recent advancements in treatment strategies have led to a significant shift in the management of this malignancy. Venetoclax, an apoptosis inducer, has emerged as a promising therapeutic option for multiple myeloma. Fatty acid oxidation (FAO) is one of the metabolic reprogramming events that occurs because of mutations in certain genes and thus plays a crucial role in cancer progression. Teglicar, a reversible inhibitor of FAO, targets carnitine palmitoyl transferase 1 (CPT1) and has shown potential in cancer treatment due to its interaction with apoptotic regulators such as Bcl-2. In this study we investigated the in vitro anti-cancer activity of teglicar, in myeloma cell lines (RPMI 8226 and U266B1). Our findings revealed a significant inhibition of RPMI 8226 cell viability with an IC50 = 50 µM, but at a higher concentration for U266B1 cells. Notably, the combination of teglicar with venetoclax showed a synergistic effect. Although both cell lines were known to be resistant to venetoclax, teglicar significantly reduced IC50 of venetoclax by 5.33 and 1.7 folds in RPMI 8226 and U266B1 respectively. In addition, single agent and combination treatment were associated with a significant increase in apoptosis in both cell lines. However, the combination therapy had no significant effect on reactive oxygen species (ROS) levels in either cell lines. Our results suggest that the combination of teglicar and venetoclax holds promise in multiple myeloma through induction of apoptosis. This study sheds light on the potential therapeutic implications of targeting FAO, specifically through CPT1 inhibition, in conjunction with apoptosis inducers for enhanced anticancer effects in multiple myeloma.

Abstract Cu immobilized onto N-doped carbon spheres (Cu/N-doped CS) derived from soybean flour was synthesized via the hydrothermal method and certified as a green high-efficiency catalyst for the regioselective synthesis of 1,4-disubstituted 1H-1,2,3-triazoles. The obtained N-doped carbon spheres from a combination of glucose and soy flour have a larger size and suitable affinity for load copper species. The morphology and structure of the as-prepared catalyst have been confirmed based on FT-IR, XRD, FE-SEM, EDX, BET, and ICP-OES characterizations. The catalytic performance of the Cu/N-doped carbon spheroids was investigated experimentally. It was found that the Cu/N-doped CS nanocomposite has a high efficiency and recyclability for 5 cycles without any appreciable loss in its catalytic activity in the synthesis of 1,4-disubstituted 1H-1,2,3-triazoles via the three-component condensation reaction of various epoxide/alkyl or aryl halides, sodium azide, and phenylacetylene in a water medium. Furthermore, significant advantages such as stability, ease of preparation, low cost of the carbon resource, high regioselectivity, and good product yield have been achieved in the heterogeneous catalyst system attractive for large-scale in many industrial products.

Abstract The development of two eco-friendly analytical methods for the simultaneous determination of eight cardiovascular drugs; hydrochlorothiazide (HCT), captopril (CPL), lisinopril (LSP), valsartan (VAL), atorvastatin (ATR), bisoprolol (BSL), amlodipine (AML) and carvedilol (CVL); alongside with the nutraceutical vincamine (VIC) is essential for sustainable pharmaceutical analysis. This study explores the application of Micellar Electro Kinetic Chromatography (MEKC) and High-Performance Liquid Chromatography (HPLC) for this purpose. In MEKC method, the separation was done using fused silica capillary (41.5 cm × 50 µm id) and a back ground electrolyte consisting of 50 mM borate buffer (pH 9) containing 50 mM sodium lauryl sulphate (SLS) and 10% organic modifier (Acetonitrile). In HPLC method, separation was performed on a ZORBAX Extend-C18 (4.6 × 250 mm, 5 µm) column, using a gradient mobile phase consisting of 50 mM phosphate buffer pH 3 and methanol. Both methods attained good linearity (r ≥ 0.9996) with low values of LOD and LOQ. Both methods were successfully applied in the determination of co-administered single, binary and ternary dosage form of the studied drugs. Moreover, application of various combinations of co-administered dosage forms was achieved in rat plasma, confirming the applicability of these methods in different matrices. The use of micellar solutions in MEKC enhances separation efficiency while reducing the need for organic solvents, aligning with green chemistry principles. HPLC methods were optimized using environmentally benign solvents, ensuring reduced toxicity and waste production. The methodologies were evaluated through green, white, and blue metrics to ensure comprehensive sustainability, considering ecological impact, safety, and practical efficiency. These methods were not only cost-effective and time-saving but achieved high efficiency, sensitivity, and reproducibility making them ideal for routine use in pharmaceutical analysis.

Abstract Cellular stress and ageing involve an increase in crowding and aggregation of amylogenic proteins. We here investigate if crowding is the intrinsic cause of aggregation and utilise a previously established non-protein aggregation sensor, namely pseudoisocyanine chloride (PIC). PIC shows fibrillization in cells into a highly fluorescent J-aggregated state and is sensitive to crowding. Surprisingly, cell stress conditions stabilise the monomeric rather than the aggregated state of PIC both in the cytoplasm and in stress granules. Regarding the different physiochemical changes of the cytoplasm occurring upon cell stress, involving volume reduction, phase separation and solidification, the intrinsic crowding effect is not the key factor to drive associated self-assembly processes.

Abstract Background There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease. Methods Plasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile. Results High cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value

This paper was to present a mathematical model of non-integer order and demonstrated the detrimental consequences of lumpy skin disease (LSD). The LSD model included primarily affected cattle and other animals, particularly buffalo and cows. Given the significant drop in the number of livestock and dairy products, it was essential to use mathematical models to raise awareness of this issue. We examined the suggested LSD model to understand as well as every possible avenue that could result in the illness spreading throughout the community. Ulam-Hyers stability made it easier to analyze the stability of the LSD model, and fixed-point theory was a valuable tool for finding the existence and uniqueness of the solution to the suggested model. We have used new versions of power law and exponential decay fractional numerical methods. Numerical calculations were showing the influence of various fractional orders on the spread of disease and provided more informations than integer orders for the sensitive parameters of the proposed model. The graphical depiction is showed an understanding of the proposed LSD model.

This paper presents a mathematical model to examine the effects of the coexistence of predators on single prey. Based on Caputo operators, we present a newly developed system of differential equations for the predator–prey system using wavelet method. It is well known that a system of nonlinear singular models cannot operate smoothly since they are singular and nonlinear. Therefore, with the help of this numerical approach, we have converted the system into a nonlinear system of algebraic equations by extending it through operational matrix of Legendre wavelets. Using the wavelet collocation scheme, we have calculated these unknown coefficients. It has been demonstrated in tables and graphs that the developed approach is consistent and proficient. Further bifurcation diagrams, as well as phase portraits, have been used to study the proposed system numerically and to analyse its behaviour. In addition, a nonlinear functional analysis have used to establish uniformly boundedness for the proposed model. Also we have discussed residual error analysis and Lyapunov exponent. The applicability and efficacy of this methodology have been demonstrated through this nonlinear system. Additionally, a comparison with existing results highlights the advantages of our numerical approach. All calculations have been done using MATLAB.

In this research, we aim to propose a non-integer order mathematical model that illustrates the detrimental impact of illegal logging on forest biomass. The model is based on the idea that soil nutrients play a vital role in the growth of forestry biomass. However, the growth of forestry biomass is hindered by the harvesting of trees for industrial expansion. To develop the model, we use a fractional order approach, which allows us to explore the impact of conservation efforts on the extension of industries. If the amount of forestry biomass that is illegally harvested exceeds a certain threshold, the system becomes unstable. To investigate the proposed model's solution, we use fixed-point theory, which is highly effective in determining the existence and uniqueness of the solution. We also use Ulam-Hyers stability to analyse the stability of the proposed model. We have also employed new versions of fractional numerical techniques using power law and exponential decay. Our proposed model provides more details through numerical calculations with fractional orders different from integer ones. Moreover, we have addressed all significant solution behaviours in the fractal-fractional system and parameter values. The graphical representation offers a better understanding of the forestry biomass model, allowing us to identify the direction and stability of solutions. From various perspectives, we analysed the features of solutions to this fractal-fractional model for stopping illegal logging.

Tumour is a very serious and dangerous health risk, which is defined as a mass or lump of tissue formalized by the aggregation of abnormal cells. In this paper, we have presented a comparative and chaotic investigation of tumour and effector cells using non-integer order tumour immune dynamical model. Also, we have looked at the interactions between different tumour cell populations and immunological composition using a model of a real-world medical research problem. Additionally, stability analysis of the proposed model is established with the help of fixed-point iteration. Further bifurcation diagrams, as well as phase portraits, have been used to study the proposed system numerically and to analyse its behaviour. For numerical simulations, we have used the Hermite wavelet operational matrix and Taufik-Atangana methods using Caputo fractional derivatives. models. The main objective of the paper is to convert nonlinear fractional systems into algebraic equations. Our findings will be valuable to biologists in cancer treatment.

Background Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. CRC deaths can be reduced with prevention and early diagnosis. Circulating tumor DNA-based liquid biopsies, are emerging tools for cancer detection. However, the tumor-signal-dependent nature of this approach results in low sensitivity in precancerous and early CRC stages. Here we propose the host immune response to the onset of cancer as an alternative approach for early detection of CRC.Methods We perform whole transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from individuals with CRC, precancerous lesions or negative colonoscopy in two independent cohorts using next-generation sequencing.Results We discover and validate novel early CRC RNA biomarkers. Taking into account, and adjusting for, the sensitivity of PBMCs transcriptomes to processing times, we report distinct transcriptomic changes in the periphery related to specific CRC stages. Activation of innate immunity is already detectable in the peripheral blood of individuals with pre-malignant advanced adenomas. This immune response is followed by signs of transient B-cell activation and sustained inhibition of T-cell responses along CRC progression, whereby at late stages, protumoral myeloid cells, wound healing and coagulation processes prevail. Moreover, some biomarkers show similar dysregulation in tumors and are implicated in known pathways of CRC pathophysiology.Conclusions The strong systemic immune modulation triggered during CRC progression leads to previously unnoticed alterations detectable in PBMCs, paving the way for the development of an early CRC screening blood test, incorporating 226 validated biomarkers identified through immunotranscriptomics.

IntroductionAging is a complex process marked by a gradual decline in physiological function and increased susceptibility to diseases. Telomere length is frequently regarded as one of the primary biomarkers of aging. Metabolic profiles are key features in longevity and have been associated with both age and age-related diseases. We previously reported an increase in the telomere length in healthy female subjects when Ramadan fasting was combined with physical training. This study aims to characterize the metabolic signature differentiating the combined effects of exercise and fasting from exercise alone and explore the correlations with the previously reported telomere length changes.MethodsTwenty-nine young, non-obese, and healthy female subjects were previously randomized into two groups: one group followed a 4-week exercise program, while the other group followed the same 4-week exercise program but also fasted during Ramadan. Metabolic profiles were assessed pre- and post-intervention using untargeted metabolomics.Results and DiscussionOur results showed a significant decrease in many lipid metabolites in the exercise-while-fasting group, particularly ceramides. Our study sheds light on the dynamic changes in lipid metabolism and its potential role in inflammation and age-related diseases, and contributes to the broader understanding of how lifestyle factors can influence cellular aging and metabolic health.

Background: Pre-diabetes, characterized by elevated glycemic indices, poses a high risk of diabetes development, and is increasingly linked to non-specific low back pain. While mechanisms remain incompletely understood, metabolic, inflammatory, and neurological factors are implicated. Dietary interventions, including low-glycemic and anti-inflammatory diets, alongside weight management, may improve outcomes in this population. Objectives: In this non-randomized controlled trial, we aim to evaluate the influence of decreasing HbA1c levels on reducing chronic non-specific low back pain in pre-diabetic, non-obese individuals, as well as emphasizing the importance of such a study in supporting the literature. Methods: A non-randomized controlled single-blind clinical trial was conducted among 82 participants with chronic non-specific low back pain and pre-diabetes at an outpatient clinic in Baghdad from the 30th of January to the 22nd of September. The intervention methods aimed at reducing HbA1c levels to assess the reduction impact on alleviating chronic non-specific low back pain included dietary adjustments, sleep optimization, and correction of vitamins and minerals deficiencies. The follow-up process was conducted individually for each participant, with a monthly assessment over a period of six months. Results: At 12 weeks a significant decrease in chronic non-specific low back pain severity was observed in patients with lower HbA1C levels yielding a P -value of .021. Similarly, at 24 weeks there was a decline in the number of patients who reported chronic non-specific low back pain, and the association to lower HbA1C levels was significant with a p -value of .005. Conclusion: This study suggests the presence of a statistically significant association between reduction of HbA1C levels and ensuing improvement in chronic non-specific low back pain symptoms in non-obese prediabetic patients.

The professional identity of scientists has historically been cultivated to value research over teaching, which can undermine initiatives that aim to reform science education. Course-Based Research Experiences (CRE) and the inclusive Research and Education Communities (iREC) are two successful and impactful reform efforts that integrate research and teaching. The aim of this study is to explicate the professional identity of instructors who implement a CRE within an established iREC and to explore how this identity contributes to the success of these programs. 97 CRE instructors from the Science Education Alliance (SEA) iREC participated in a 2-year, multi-stage, qualitative research project that involved weekly reflective journaling, autoethnographic description, small group evaluation and writing, and large-scale community checking. The resulting description of professional identity consisted of shared values (inclusivity, student success, community membership, ownership/agency, science, overcoming failure, and persistence), specified roles (mentor, advocate, scientist, educator, motivator, collaborator, community builder, learner, evaluator and project manager) and a stated sense of self (dedicated, resilient, pride in students, multiskilled, valued, community member, responsible and overworked). Analysis of individual reflective diary entries revealed how a professional identity underpinned and facilitated the ways in which faculty addressed challenges that arose and worked toward the success of every student. It is the self-concept of the professional identity of the instructor in the context of the CRE classroom that directed the extended commitment and effort that these instructors evidently put into their work with students, which facilitated student engagement, student persistence, and their collective scientific output. The study concludes that a professional identity of STEM faculty in the context of a CRE and iREC combines being a researcher and educator, and that this integrated identity is central for current initiatives aimed at transforming undergraduate STEM education.

Abstract Natural products play a significant role in providing the current demand as antiparasitic agents, which offer an attractive approach for the discovery of novel drugs. The present study aimed to evaluate in vitro the potential impact of seaweed Padina pavonica (P. pavonica) extract in combating Acanthamoeba castellanii (A. castellanii). The phytochemical constituents of the extract were characterized by Gas chromatography–mass spectrometry. Six concentrations of the algal extract were used to evaluate its antiprotozoal activity at various incubation periods. Our results showed that the extract has significant inhibition against trophozoites and cysts viability, with complete inhibition at the high concentrations. The IC50 of P. pavonica extract was 4.56 and 4.89 µg/mL for trophozoites and cysts, respectively, at 24 h. Morphological alterations of A. castellanii trophozoites/cysts treated with the extract were assessed using inverted and scanning electron microscopes and showed severe damage features upon treatment with the extract at different concentrations. Molecular Docking of extracted compounds against Acanthamoeba cytochrome P450 monooxygenase (AcCYP51) was performed using Autodock vina1.5.6. A pharmacokinetic study using SwissADME was also conducted to investigate the potentiality of the identified bioactive compounds from Padina extract to be orally active drug candidates. In conclusion, this study highlights the in vitro amoebicidal activity of P. pavonica extract against A. castellanii adults and cysts and suggests potential AcCYP51 inhibition.

Abstract Background This study investigates the genetic characteristics of Capillaria isolates from the infected fish, Bagrus bajad, and their relation to human Capillaria philippinensis using Random Amplified Polymorphic DNA (RAPD-PCR) analysis. Fifteen fish Capillaria were isolated and compared to identified human C. philippinensis using six primers: M-are, M-1, G-7, G-11, G-15, and G-18. Results All six primers successfully amplified DNA, highlighting their efficacy in distinguishing between human and fish Capillaria isolates. The analysis revealed distinctive banding patterns between fish and human isolates, with variations in size and number of DNA fragments. Additionally, genetic similarity analysis showed intriguing patterns of relatedness, with certain pairs exhibiting high similarity percentages. Comparative assessment of RAPD polymorphism demonstrated consistent findings of 100% polymorphism across all primers. The Unweighted Pair Group Method with Arithmetic Mean Algorithm (UPGMA) evaluated the closest relationship between human and fish isolates. These results underscore the utility of RAPD analysis in delineating the genetic diversity among Capillaria isolates from different hosts. Conclusion Overall, this study contributes to our understanding of the genetic variability and relatedness among Capillaria isolates, shedding light on their evolutionary dynamics and zoonotic potential.

BackgroundSulfonylureas have been a longstanding pharmacotherapy in the management of type 2 diabetes, with potential benefits beyond glycemic control. Although sulfonylureas are effective, interindividual variability exists in drug response. Pharmacometabolomics is a potent method for elucidating variations in individual drug response. Identifying unique metabolites associated with treatment response can improve our ability to predict outcomes and optimize treatment strategies for individual patients. Our objective is to identify metabolic signatures associated with good and poor response to sulfonylureas, which could enhance our capability to anticipate treatment outcome.MethodsIn this cross-sectional study, clinical and metabolomics data for 137 patients with type 2 diabetes who are taking sulfonylurea as a monotherapy or a combination therapy were obtained from Qatar Biobank. Patients were empirically categorized according to their glycosylated hemoglobin levels into poor and good responders to sulfonylureas. To examine variations in metabolic signatures between the two distinct groups, we have employed orthogonal partial least squares discriminant analysis and linear models while correcting for demographic confounders and metformin usage.ResultsGood responders showed increased levels of acylcholines, gamma glutamyl amino acids, sphingomyelins, methionine, and a novel metabolite 6-bromotryptophan. Conversely, poor responders showed increased levels of metabolites of glucose metabolism and branched chain amino acid metabolites.ConclusionThe results of this study have the potential to empower our knowledge of variability in patient response to sulfonylureas, and carry significant implications for advancing precision medicine in type 2 diabetes management.

Background: The prevalence and burden of mental illness among young people is rising, globally. Youth mental health services, such as headspace, offer young people access to multidisciplinary mental healthcare, specifically designed to address their needs. Pharmacists are medicines experts and possess a skillset increasingly being utilised in expanded areas of practice. There is potential for pharmacists to perform roles within youth mental health services, however sparse literature exploring pharmacist-delivered mental healthcare for young people exists. Objective: To explore views of headspace staff on medication use among young people who use youth mental health services and pharmacists' potential roles within the headspace youth mental health service model. Methods: Individual semi-structured interviews were conducted with staff from one inner city headspace centre in Sydney, Australia. An interview guide was developed to capture participants' views on medication use among young people using youth mental health services and potential roles for pharmacists within this context. Reflexive thematic analysis was conducted to analyse the findings of this exploratory pilot study. Results: Twelve staff members were interviewed, allowing for a range of multidisciplinary perspectives. Four themes were identified from the data: (i) gaps in medication-related care, (ii) potential roles for pharmacists at headspace (iii) collaboration between pharmacists and general practitioners, and (iv) a “one-stop shop”. Conclusions: There are opportunities for pharmacists to improve young peoples' experiences using psychotropic medications through the provision of medication information to clients and caregivers. Pharmacists have a potential role to play in contributing to multidisciplinary case reviews but clarifying their specific roles when working alongside general practitioners is necessary. Uncertainty regarding the feasibility of pharmacist-led services within the headspace youth mental health service model and a lack of awareness regarding pharmacists' full scope of practice are barriers to pharmacists' potential roles within the headspace model.

Abstract Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Abstract In this study, the efficacy of the promising iron—based polymeric inorganic coagulant (POFC) was assessed for the reduction of eutrophication effect (freshwater toxicity) and the microbial loads from wastewater. Toxicity assessment for POFC was conducted on mice and skin cell lines. The results confirm the lower toxicity level of POFC. The POFC showed excellent antibacterial efficacy against Gram-positive and Gram-negative bacteria. Moreover, it demonstrated a remarkable effectiveness against black fungus such as Aspergillus niger and Rhizopus oryzae. Additionally, POFC showed antiviral effectiveness against the highly pathogenic H5N1 influenza virus as well as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). POFC-based treatment gives excellent removal percentages for phosphate, and phosphorus at doses below 60 ppm with a low produced sludge volume that leads to 84% decrease in the rate of eutrophication and freshwater toxicity. At a POFC concentration of 60 ppm, remarkable reduction rates for total coliforms, fecal coliforms, and E. coli were achieved. After POFC-based coagulation, the produced sludge retains a lower bacterial density due to the antibacterial activity of POFC. Furthermore, it revealed that the observed removal efficiencies for fungi and yeasts in the produced sludge reached 85% at a POFC dose of 60 ppm. Overall, our research indicates that POFC has potential for application in pre-treatment of wastewater and serves as an antimicrobial agent.

Abstract Repeat vaccination with egg-based influenza vaccines could preferentially boost antibodies targeting the egg-adapted epitopes and reduce immunogenicity to circulating viruses. In this randomized trial (Clinicaltrials.gov: NCT03722589), sera pre- and post-vaccination with quadrivalent inactivated egg-based (IIV4), cell culture-based (ccIIV4), and recombinant (RIV4) influenza vaccines were collected from healthcare personnel (18-64 years) in 2018−19 (N = 723) and 2019−20 (N = 684) influenza seasons. We performed an exploratory analysis. Vaccine egg-adapted changes had the most impact on A(H3N2) immunogenicity. In year 1, RIV4 induced higher neutralizing and total HA head binding antibodies to cell- A(H3N2) virus than ccIIV4 and IIV4. In year 2, among the 7 repeat vaccination arms (IIV4-IIV4, IIV4-ccIIV4, IIV4-RIV4, RIV4-ccIIV4, RIV4-RIV4, ccIIV4-ccIIV4 and ccIIV4-RIV4), repeat vaccination with either RIV4 or ccIIV4 further improved antibody responses to circulating viruses with decreased neutralizing antibody egg/cell ratio. RIV4 also had higher post-vaccination A(H1N1)pdm09 and A(H3N2) HA stalk antibodies in year 1, but there was no significant difference in HA stalk antibody fold rise among vaccine groups in either year 1 or year 2. Multiple seasons of non-egg-based vaccination may be needed to redirect antibody responses from immune memory to egg-adapted epitopes and re-focus the immune responses towards epitopes on the circulating viruses to improve vaccine effectiveness.

Abstract The Santa Barbara Basin is an extraordinary archive of environmental and ecological change, where varved sediments preserve microfossils that provide an annual to decadal record of the dynamics of surrounding ecosystems. Of the microfossils preserved in these sediments, benthic foraminifera are the most abundant seafloor-dwelling organisms. While they have been extensively utilized for geochemical and paleoceanographic work, studies of their morphology are lacking. Here we use a high-throughput imaging method (AutoMorph) designed to extract 2D data from photographic images of fossils to produce a large image and 2D shape dataset of recent benthic foraminifera from two core records sampled from the center of the Santa Barbara Basin that span an ~800-year-long interval during the Common Era (1249–2008 CE). Information on more than 36,000 objects is included, of which more than 22,000 are complete or partially-damaged benthic foraminifera. The dataset also includes other biogenic microfossils including ostracods, pteropods, diatoms, radiolarians, fish teeth, and shark dermal denticles. We describe our sample preparation, imaging, and identification techniques, and outline potential data uses.

Background: A major drawback of resin composites is their tendency to accumulate microbial biofilms that can lead to secondary caries. The objective of this study was to compare the mechanical properties and the degree of conversion of commercial resin-based composite materials containing a contact-killing antibacterial agent, dimethylaminohexadecyl methacrylate (DMAHDM), at different concentrations, with a fluoride-releasing composite material. Materials and methods: Four groups were tested: Tetric N Ceram composite material (G1), Tetric Evo Ceram (G2), and Tetric N Ceram with the addition of contact-killing antibacterial agent DMAHDM at concentrations of 3% (G3) and 5% (G4). The mechanical properties, including flexural strength, elastic modulus, and Vickers microhardness and the degree of conversion were investigated. Results: Adding 3 % and 5 % DMAHDM resulted in flexural strength values that were comparable to Tetric Evo Ceram. Tetric N Ceram was comparable to the group containing 3 % DMAHDM (p > 0.05). However, it was significantly greater when compared to Tetric Evo Ceram (93.3 ± 9.4) and 5 % DMAHDM (p 0.05). There was no statistically significant difference in the degree of conversion between the groups (p > 0.05). Conclusion: Adding 3% DMAHDM to Tetric N Ceram resulted in flexural strength values that were similar to those of Tetric N Ceram and Tetric Evo Ceram. DMAHDM did not affect the degree of conversion of Tetric N Ceram composite.

Objectives: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) patients experience a lower quality of life, frequent exacerbations, and worse pulmonary function. Environmental management is essential in a complex chronic condition, as pollutant exposure can worsen symptoms and increase morbidity and mortality. We aimed to identify evidence that informs nursing interventions in promoting self-management of air quality in asthmatic people with COPD. Methods: We conducted an integrative review in March of 2023. We searched the databases CINAHL, MEDLINE, Academic Search Complete, Cochrane Database of Systematic Reviews (CDSR), Scopus, Web of Science, Joanna Briggs Institute (JBI) Evidence-Based Practice Database, and Google Scholar. We included articles whose participants were adults with asthma, COPD, or both; the intervention was air quality management and the outcome of any exacerbations. We excluded editorials, letters, commentaries, opinion papers, position papers, study protocols, conference abstracts, and reviews. Data extraction and synthesis were performed, categorizing interventions according to nursing actions. Methodological quality assessment was conducted using the JBI Critical Appraisal Checklist tools. The review protocol was registered at Open Science Framework (https://doi.org/10.17605/OSF.IO/5Y4KW). Results: We included five articles from different countries. The interventions promoting air quality self-management for individuals with asthma and COPD included vigilance interventions (health professional regular visits, assessment of symptoms), monitoring interventions (measurement of indoor and outdoor trigger factors), and educational interventions (air quality alerts, allergen avoidance). Policy interventions such as smoke-free policies and comprehensive strategies to improve air quality were also identified. These areas of focus represent critical components of nurses’ interventions and can integrate the fundamental patterns of knowing in nursing. Although the studies reveal heterogeneous interventions and the methodological quality is variable, these interventions showed potential for preventing exacerbations, reducing emergency department visits, and minimizing hospitalizations. Conclusions: The study emphasizes the need for a comprehensive approach involving nurses in multidisciplinary teams to air quality self-management. They can use these results to inform their interventions and ways of knowing, benefiting individuals with asthma and COPD. Further research is needed to expand the evidence base and refine these interventions.

In recent studies, platform ecosystems, an extension of business ecosystems, have emerged as highly disruptive mechanisms for generating value within various industries. The transformative influence of digital technologies on conventional business landscapes is increasingly evident, facilitating inclusive and sustainable development. However, realizing value co-creation within digital platform ecosystems faces formidable hurdles in healthcare, primarily attributed to the complex challenges surrounding privacy, security, and effective data governance. Following the Joanna Briggs Institute Guidelines for scoping reviews, the study explores the extent literature on the integration of digital platform ecosystems in healthcare. The contribution of this article is to explore the applications of platform ecosystems in healthcare delivery, specifically focusing on electronic healthcare records, smartphones, artificial intelligence, big data, the Internet of Things, and blockchain technologies. The research identifies and discusses the challenges of implementing these technologies in the healthcare industry. Furthermore, the study proposes a healthcare platform ecosystem framework, integrating communication strategies, GDPR compliance, and architectural components. This study synthesizes the extant literature to formulate a theoretical healthcare ecosystem framework for improved patient-centric care. The review and resultant framework is intended to support understanding of digital health dynamics and guides healthcare organizations, technology developers, and policymakers in ensuring data security, compliance and interoperability.

Cecal volvulus is a rare and life-threatening cause of intestinal obstruction with multiple risk factors including prior abdominal surgery and cecal hypermobility. Although its incidence has been reported after common procedures such as cholecystectomy and appendectomy, it has not been well studied after laparoscopy, especially in gynecological surgeries. If untreated, a cecal volvulus can result in serious complications such as intestinal strangulation, necrosis, or perforation. Therefore, early identification of risk factors and intervention is important in prevention of these sequelae. Here, we report a case of cecal volvulus in a patient with endometrial carcinoma after a staging robotic-assisted laparoscopic hysterectomy and the risk factors that may have led to her complication.

In the last few decades, academic research has focused more on financial problems and poverty levels. These are among the two major challenges of the modern world today. To understand the challenge of financial crisis and poverty in societies. This paper explains a deterministic financial system of non linear differential equations. Which aim to provide recommendations to address the twin challenges. In this fractional chaotic model, memory and chaos are portrayed as effects on a system. Financial systems of fractional order have three compartments: interest rate x(t), investment demand rate y(t) and price indexes rate z(t). For the first time, the Legendre wavelet approximation is applied to fractional order financial systems. A major objective of this process is to convert fractional differential equations (FDEs) into algebraic equations by using Legendre wavelets and their fractional integral operators. For residual analysis, convergence and stability analysis, we have used iteration methods and Legendre wavelets. This study indicates good results between the approximate and numerical solutions and that this method is efficient and accurate. Using the iteration method, we prove that the solution exists, while the contraction theory proves its uniqueness. The findings of this study will be extremely useful for future financial management. We have demonstrated the applicability and effectiveness of these methods by analysing numerical simulations for the fractional order financial model and the numerical simulation has been calculated by MATLAB programming.

Abstract Objective Otitis media with effusion is common in children with cleft palates. This study aimed to investigate the link between palatal closure techniques and audiological outcomes. Methods In this retrospective‐prospective cohort study, we examined the relationship between palate repair techniques and hearing outcomes in children with cleft palates. From 2017 to 2022, 190 ears of 95 cleft patients were studied at the Cleft Lip and Palate Department of Shiraz University of Medical Sciences. Variables assessed included the surgical technique, cleft severity, auditory brainstem response (ABR) threshold, and tympanometry configuration. Results The mean ABR improved from a prepalatoplasty value of 39.51(11.62) decibels (dB) to a postpalatoplasty mean of 26.61(11.60) dB (Cohen's d: 1.12 [95% CI; 0.90–1.34]). Initially, 87.9% of the studied ears exhibited abnormal tympanometry, but this significantly decreased to 47% postsurgery (risk ratio: 4.43 [95% CI; 1.20–16.43]). When compared with Sommerlad intravelar veloplasty, the Nadjmi modified Furlow palatoplasty was associated with a notably lower mean ABR (β: −6.58 [95% CI: −10.43 to −2.73], p‐value = .001) and a reduced frequency of abnormal tympanometry (odds ratio [OR]: −1.10; 95% CI: −1.85 to −0.36, p‐value = .004). Factors like prepalatoplasty ABR, cleft palate severity, gender, and syndromic did not confound these findings. Conclusions Although the Nadjmi modified Furlow palatoplasty showed better results, our findings indicate a significant improvement in ABR and tympanometry outcomes for both techniques. Future randomized controlled trials are suggested to confirm the influence of palatal closure techniques on audiological outcomes. Level of Evidence 3b.

Introduction Clinical pharmacy services often involve multifaceted pharmacist-led interventions. However, current pharmacy practice models vary across different countries. Despite the documented benefits of clinical pharmacy services, the characteristics of pharmacist-led interventions in different countries have not yet been adequately explored and described. Therefore, this protocol outlines the methodology for a proposed scoping review aiming to investigate various types of multifaceted pharmacist-led interventions and the outcomes used to evaluate their effectiveness within secondary care settings. Additionally, the scoping review will map the current evidence surrounding the characteristics of interventions and outcomes reported across various countries of socioeconomic status.Methods and analysis The scoping review will be conducted according to the JBI Methodology for Scoping Reviews and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Extension for Scoping Reviews. We will systematically search the following electronic databases: MEDLINE (Ovid), CINAHL (EbscoHost), Embase (embase.com), Scopus (scopus.com), Cochrane Library (cochranelibrary.com) and APA PsycInfo (Ovid). Additionally, the reference lists of identified reviews and included full texts will be searched for relevant papers. Grey literature sources, such as International Pharmaceutical Abstracts and the International Pharmaceutical Federation (FIP) website, will be searched. We will include primary studies published in the English language from January 2013 to December 2023, involving secondary care multifaceted pharmacist-led interventions. Two independent reviewers will screen studies against eligibility criteria and use a piloted data extraction form to extract relevant information. We will extract relevant data, complete a tabular summary from each included publication and analyse it.Ethics and dissemination Ethical approval is not required as we will be using data from publicly available literature sources. Findings will be disseminated in publications and presentations with relevant stakeholders. We aim to map available evidence across the breadth of studies that have reported multifaceted pharmacist-led interventions and their outcomes.

Background: Prostate cancer (PCa) is one of the leading diseases causing mortality. It comes in the third rank of common cancer types. It is considered extremely a complicated cancer type since it occurs in highly steroid-responsive and dependent tissues. Many factors are considered to play an important role in the disease progression of PCa, with some functioning at the molecular level. Methodology: After applying the exclusion criteria, 200 patients who underwent proctectomy were included in this study. Following receiving patient consent, blood samples were withdrawn from patients, DNA was extracted, and precise polymerase chain reaction (PCR) amplification was conducted using specifically designed primers. The resulting amplicons were sequenced and analyzed. Results: The progesterone receptor B (PGRB) DNA from patients showed four distinctive single-nucleotide polymorphisms (SNPs) at sites 11:101128812, 11:101128924, 11:101128949, and 11:101128986, which altered the amino acid sequences to Y>N, A>D, T>I, and C>R, respectively, compared to control. These SNPs resided in sensitive sites that either affected the control elements or promoted alterations in the protein configuration. This DNA change diminished the PGR gene function and promoted an imbalance in the encoded PGR protein structure and expression. Conclusions: Many factors may play a role in PCa manifestation, with steroids and progesterone initially noted as factors. Many studies have dealt with the hormonal effect on PCa; however, few have ultimately determined the molecular impact on disease progression. The presence of pathogenic SNPs in the enhancing region of the gene may impact the expression level of PGR. High or low expression levels may negatively affect gene function, which can be considered a reliable factor in prostate tumorigenesis.

Introduction: Non-invasive assays are needed to better discriminate patients with prostate cancer (PCa) to avoid over-treatment of indolent disease. We analyzed 14 methylated DNA markers (MDMs) from urine samples of patients with biopsy-proven PCa relative to healthy controls and further studied discrimination of clinically significant PCa (csPCa) from healthy controls and Gleason 6 cancers. Methods: To evaluate the panel, urine from 24 healthy male volunteers with no clinical suspicion for PCa and 24 men with biopsy-confirmed disease across all Gleason scores was collected. Blinded to clinical status, DNA from the supernatant was analyzed for methylation signal within specific DNA sequences across 14 genes (HES5, ZNF655, ITPRIPL1, MAX.chr3.6187, SLCO3A1, CHST11, SERPINB9, WNT3A, KCNB2, GAS6, AKR1B1, MAX.chr3.8028, GRASP, ST6GALNAC2) by target enrichment long-probe quantitative-amplified signal assays. Results: Utilizing an overall specificity cut-off of 100% for discriminating normal controls from PCa cases across the MDM panel resulted in 71% sensitivity (95% CI: 49–87%) for PCa detection (4/7 Gleason 6, 8/12 Gleason 7, 5/5 Gleason 8+) and 76% (50–92%) for csPCa (Gleason ≥ 7). At 100% specificity for controls and Gleason 6 patients combined, MDM panel sensitivity was 59% (33–81%) for csPCa (5/12 Gleason 7, 5/5 Gleason 8+). Conclusions: MDMs assayed in urine offer high sensitivity and specificity for detection of clinically significant prostate cancer. Prospective evaluation is necessary to estimate discrimination of patients as first-line screening and as an adjunct to prostate-specific antigen (PSA) testing.

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The study cohort included non-obese individuals from the Qatar Biobank categorized into three groups: insulin sensitive, insulin resistant, and patients with T2D. Each group comprised 236 participants, totaling 708 individuals. Metabolomic profiling was conducted using high-resolution mass spectrometry, and statistical analyses were performed to identify metabolites associated with the progression from IS to IR and T2D. The study observed significant alterations in specific phospholipid metabolites across the IS, IR, and T2D groups. Choline phosphate, glycerophosphoethanolamine, choline, glycerophosphorylcholine (GPC), and trimethylamine N-oxide showed significant changes correlated with disease progression. A distinct metabolic signature in non-obese individuals with IR and T2D was characterized by shifts in choline metabolism, including decreased levels of choline and trimethylamine N-oxide and increased levels of phosphatidylcholines, phosphatidylethanolamines, and their degradation products. These findings suggest that alterations in choline metabolism may play a critical role in the development of glucose intolerance and insulin resistance. Targeting choline metabolism could offer potential therapeutic strategies for treating T2D. Further research is needed to validate these biomarkers and understand their functional significance in the pathogenesis of IR and T2D in non-obese populations.

The Pb2+ ions biosorption removal onto dead biomass of Chlorophyta algae is optimized by employing response surface methodology (RSM). Central composite design (CCD)-based experiments were carried out, and RSM was used to evaluate the results. The effects of contact time (15-120min), with pH solution (2-7), initial lead concentration (25-100 mg/L), biomass dose (0.01-1 g/100 mL), agitation speed (100-300 rpm) on the biosorption process were investigated. The optimal conditions of the experimental, data were pH (5), metal concentration (50mg/L), dosage (0.2g/100mL), agitation speed (200 rpm), and contact time of 120 min with constant particle size (63 mm), which gave 98.88% removal efficiency. All the variables and reactions in the biosorption experiments were evaluated using the desirability function to determine the optimal point at which the desired parameters may be attained. The promising results obtained indicate the potential use of Chlorphyta green macroalgae to treat industrial wastewater polluted with toxic metals.

IntroductionNational health policies to stop the spread of the COVID-19 virus in the US resulted in widespread school closures and disrupted learning in Spring 2020.MethodsThis study draws on unique individual-level data from n = 282 5–12 year olds enrolled in the NIH Environmental influences on Child Health Outcomes (ECHO) Research Program to investigate associations between caregiver-reported duration of Spring 2020 learning disruptions and academic achievement.ResultsLinear regression analyses estimated that children who experienced more than 4 weeks of instruction disruptions in Spring 2020 scored 4.5 points [95% CI: −8.77, −0.22] lower on age-normed math assessments compared to peers who had four or fewer weeks of disruption, adjusting for sociodemographic variables, pre-pandemic vocabulary, and COVID-19 family hardships and stress. No differences were found for reading. Children whose caregivers had higher levels of pandemic-related traumatic stress and lower educational attainment also had lower math scores, adjusting for all other covariates.DiscussionResults suggest educators and schools focus additional attention on supporting math instruction for children who experienced extended learning disruptions.

Shiga toxin (Stx)-producing Escherichia coli (STEC) of non-O157:H7 serotypes are responsible for global and widespread human food-borne disease. Among these serogroups, O26, O45, O103, O111, O121, and O145 account for the majority of clinical infections and are colloquially referred to as the “Big Six.” The “Big Six” strain panel we sequenced and analyzed in this study are reference type cultures comprised of six strains representing each of the non-O157 STEC serogroups curated and distributed by the American Type Culture Collection (ATCC) as a resource to the research community under panel number ATCC MP-9. The application of long- and short-read hybrid sequencing yielded closed chromosomes and a total of 14 plasmids of diverse functions. Through high-resolution comparative phylogenomics, we cataloged the shared and strain-specific virulence and resistance gene content and established the close relationship of serogroup O26 and O103 strains featuring flagellar H-type 11. Virulence phenotyping revealed statistically significant differences in the Stx-production capabilities that we found to be correlated to the strain’s individual stx-status. Among the carried Stx1a, Stx2a, and Stx2d phages, the Stx2a phage is by far the most responsive upon RecA-mediated phage mobilization, and in consequence, stx2a + isolates produced the highest-level of toxin in this panel. The availability of high-quality closed genomes for this “Big Six” reference set, including carried plasmids, along with the recorded genomic virulence profiles and Stx-production phenotypes will provide a valuable foundation to further explore the plasticity in evolutionary trajectories in these emerging non-O157 STEC lineages, which are major culprits of human food-borne disease.

Abstract Background Research and clinical practice rely heavily on caregiver‐report measures, such as the Child Behavior Checklist 1.5–5 (CBCL/1.5‐5), to gather information about early childhood behavior problems and to screen for child psychopathology. While studies have shown that demographic variables influence caregiver ratings of behavior problems, the extent to which the CBCL/1.5‐5 functions equivalently at the item level across diverse samples is unknown. Methods Item‐level data of CBCL/1.5‐5 from a large sample of young children (N = 9087) were drawn from 26 cohorts in the Environmental influences on Child Health Outcomes program. Factor analyses and the alignment method were applied to examine measurement invariance (MI) and differential item functioning (DIF) across child (age, sex, bilingual status, and neurodevelopmental disorders), and caregiver (sex, education level, household income level, depression, and language version administered) characteristics. Child race was examined in sensitivity analyses. Results Items with the most impactful DIF across child and caregiver groupings were identified for Internalizing, Externalizing, and Total Problems. The robust item sets, excluding the high DIF items, showed good reliability and high correlation with the original Internalizing and Total Problems scales, with lower reliability for Externalizing. Language version of CBCL administration, education level and sex of the caregiver respondent showed the most significant impact on MI, followed by child age. Sensitivity analyses revealed that child race has a unique impact on DIF over and above socioeconomic status. Conclusions The CBCL/1.5‐5, a caregiver‐report measure of early childhood behavior problems, showed bias across demographic groups. Robust item sets with less DIF can measure Internalizing and Total Problems equally as well as the full item sets, with slightly lower reliability for Externalizing, and can be crosswalked to the metric of the full item set, enabling calculation of normed T scores based on more robust item sets.

Until recently, the study of age-related decline in fertility has focused primarily on the ovary; depletion of the finite pool of oocytes and increases in meiotic errors leading to oocyte aneuploidy are well-established mechanisms by which fertility declines with advancing age. Comparatively little is known about the impact of age on endometrial function. The endometrium is a complex tissue comprised of many cell types, including epithelial, stromal, vascular, immune and stem cells. The capacity of this tissue for rapid, cyclic regeneration is unique to this tissue, undergoing repeated cycles of growth and shedding (in the absence of an embryo) in response to ovarian hormones. Furthermore, the endometrium has been shown to be capable of supporting pregnancies beyond the established boundaries of the reproductive lifespan. Despite its longevity, molecular studies have established age-related changes in individual cell populations within the endometrium. Human clinical studies have attempted to isolate the effect of aging on the endometrium by analyzing pregnancies conceived with euploid, high quality embryos. In this review, we explore the existing literature on endometrial aging and its impact on pregnancy outcomes. We begin with an overview of the principles of endometrial physiology and function. We then explore the mechanisms behind endometrial aging in its individual cellular compartments. Finally, we highlight lessons about endometrial aging gleaned from rodent and human clinical studies and propose opportunities for future study to better understand the contribution of the endometrium to age-related decline in fertility.

Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis. Therefore, this study aimed to assess the therapeutic potential of Capsaicin as an additional treatment to enhance patient tolerance to Bleomycin compared to the antifibrotic drug Pirfenidone. Pulmonary fibrosis was induced in rats through by a single intratracheal Bleomycin administration in day zero, followed by either Capsaicin or Pirfenidone treatment for 7 days. After the animals were sacrificed, their lungs were dissected and examined using various stains for macroscopic and histopathological evaluation. Additionally, the study assessed various antioxidant, anti-inflammatory, and antifibrotic parameters were assessed. Rats exposed to Bleomycin exhibited visible signs of fibrosis, histopathological alterations, increased collagen deposition, and elevated mucin content. Bleomycin also led to heightened increased inflammatory cells infiltration in the bronchoalveolar lavage, elevated fibrosis biomarkers such as hydroxyproline, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β1), increased inflammatory markers including tumor necrosis factor-alpha (TNF-α), interlukine-6 (Il-6), interlukine-1β (Il-1β) nuclear factor-kappa B (NF-κB), and Cyclooxygenase-2 (COX-2), and transforming growth factor-beta (TGF-β1),. Furthermore, it reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), increased oxidative stress biomarkers like nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and protein carbonyl. Bleomycin also decreased the expression of nuclear factor erythroid 2–related factor 2 (Nrf-2), reduced glutathione (GSH), total antioxidant capacity, and the activities of catalase and superoxide dismutase (SOD). Treating the animals with Capsaicin and Pirfenidone following Bleomycin exposure resulted in improved lung macroscopic and microscopic characteristics, reduced collagen deposition (collagen I and collagen III) and mucin content, decreased inflammatory cell infiltration, lowered levels of hydroxyproline, α-SMA, and TGF-β1, decreased TNF-α, Il-6, Il-1β, NF-κB, and COX-2, increased PPAR-γ and Nrf-2 expression, and improvement improved in all oxidative stress biomarkers. In summary, Capsaicin demonstrates significant antifibrotic activity against Bleomycin-induced lung injury that may be attributed, at least in part, to the antioxidant and anti-inflammatory activities of Capsaicin mediated by upregulation of PPAR-γ and Nrf-2 expression and decreasing. TGF-β1, NF-κB and COX II proteins concentrations.

This paper aims to provide an understanding of the dynamics and behavior of the financial model in the context of fractional differential equations. The model explores the interactions and connections among four key financial variables: interest rates, investment demand, price index, and savings amounts. We establish the existence of unique solution for the fractional financial model and stability of the model using iterative approach by employing Banach’s fixed point theory. A numerical method is carried out to perform the numerical simulation of the Caputo–Fabrizio financial model. The work capitalizes on the insights gained by scrutinizing the repercussions stemming from variations in model parameters on the dynamics of the solutions obtained through our numerical scheme. Our findings highlight that the interplay among diverse financial components can lead to chaotic behavior in specific scenarios.

IntroductionDeprescribing fall-risk increasing drugs (FRIDs) is promising for reducing the risk of falling in older adults. Applying appropriate deprescribing in practice can be difficult due to the outcome uncertainties associated with stopping FRIDs. The ADFICE_IT intervention addresses this complexity with a clinical decision support system (CDSS) that facilitates optimum deprescribing of FRIDs by using a fall-risk prediction model, aggregation of deprescribing guidelines, and joint medication management.MethodsThe development process of the CDSS is described in this paper. Development followed a user-centered design approach in which users and experts were involved throughout each phase. In phase I, a prototype of the CDSS was developed which involved a literature and systematic review, European survey (n = 581), and semi-structured interviews with clinicians (n = 19), as well as the aggregation and testing of deprescribing guidelines and the development of the fall-risk prediction model. In phase II, the feasibility of the CDSS was tested by means of two usability testing rounds with users (n = 11).ResultsThe final CDSS consists of five web pages. A connection between the Electronic Health Record allows for the retrieval of patient data into the CDSS. Key design requirements for the CDSS include easy-to-use features for fast-paced clinical environments, actionable deprescribing recommendations, information transparency, and visualization of the patient's fall-risk estimation. Key elements for the software include a modular architecture, open source, and good security.ConclusionThe ADFICE_IT CDSS supports physicians in deprescribing FRIDs optimally to prevent falls in older patients. Due to continuous user and expert involvement, each new feedback round led to an improved version of the system. Currently, a cluster-randomized controlled trial with process evaluation at hospitals in the Netherlands is being conducted to test the effect of the CDSS on falls. The trial is registered with ClinicalTrials.gov (date; 7-7-2022, identifier: NCT05449470).

Dental caries is a prevalent chronic disease among adolescents. Caries activity increases significantly during adolescence due to an increase in susceptible tooth surfaces, immature permanent tooth enamel, independence in pursuing self-care, and a tendency toward poor diet and oral hygiene. Dental caries in permanent teeth is more prevalent among adolescents in low-income families and racial/ethnic minority groups, and these disparities in adolescent dental caries experience have persisted for decades. Several conceptual and data-driven models have proposed unidirectional mechanisms that contribute to the extant disparities in adolescent dental caries experience. Our objective, using a literature review, is to provide an overview of risk factors contributing to adolescent dental caries. Specifically, we map the interactive relationships of multilevel factors that influence dental caries among adolescents. Such interactive multilevel relationships more closely reflect the complex nature of dental caries experience among the adolescent population. The methods that we use are two-fold: (1) a literature review using PubMed and Cochrane databases to find contributing factors; and (2) the system dynamics approach for mapping feedback mechanisms underlying adolescent dental caries through causal loop diagramming. The results of this study, based on the review of 138 articles, identified individual, family and community-level factors and their interactions contributing to dental caries experience in adolescents. Our results also provide hypotheses about the mechanisms underlying persistence of dental caries among adolescents.ConclusionsOur findings may contribute to a deeper understanding of the multilevel and interconnected factors that shape the persistence of dental caries experience among adolescents.

Hybrid immunity (vaccination + natural infection) to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. The mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed for T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera, reflected by smaller antigenic cartography distances. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B- and T-cell responses.

The endometrium is a resilient and highly dynamic tissue, undergoing cyclic renewal in preparation for embryo implantation. Cyclic endometrial regeneration depends on the intact function of several cell types, including parenchymal, endothelial, and immune cells, as well as adult stem cells that can arise from endometrial or extrauterine sources. The ability of the endometrium to undergo rapid, repeated regeneration without scarring is unique to this tissue. However, if this tissue renewal process is disrupted or dysfunctional, women may present clinically with infertility due to endometrial scarring or persistent atrophic/thin endometrium. Such disorders are rate-limiting in the treatment of female infertility and in the success of in vitro fertilization because of a dearth of treatment options specifically targeting the endometrium. A growing number of studies have explored the potential of adult stem cells, including mesenchymal stem cells (MSCs), to treat women with disorders of endometrial regeneration. MSCs are multipotent adult stem cells with capacity to differentiate into cells such as adipocytes, chondrocytes, and osteoblasts. In addition to their differentiation capacity, MSCs migrate toward injured sites where they secrete bioactive factors (e.g. cytokines, chemokines, growth factors, proteins and extracellular vesicles) to aid in tissue repair. These factors modulate biological processes critical for tissue regeneration, such as angiogenesis, cell migration and immunomodulation. The MSC secretome has therefore attracted significant attention for its therapeutic potential. In the uterus, studies utilizing rodent models and limited human trials have shown a potential benefit of MSCs and the MSC secretome in treatment of endometrial infertility. This review will explore the potential of MSCs to treat women with impaired endometrial receptivity due to a thin endometrium or endometrial scarring. We will provide context supporting leveraging MSCs for this purpose by including a review of mechanisms by which the MSC secretome promotes regeneration and repair of nonreproductive tissues.

Abstract Introduction Research driven by real‐world clinical data is increasingly vital to enabling learning health systems, but integrating such data from across disparate health systems is challenging. As part of the NCATS National COVID Cohort Collaborative (N3C), the N3C Data Enclave was established as a centralized repository of deidentified and harmonized COVID‐19 patient data from institutions across the US. However, making this data most useful for research requires linking it with information such as mortality data, images, and viral variants. The objective of this project was to establish privacy‐preserving record linkage (PPRL) methods to ensure that patient‐level EHR data remains secure and private when governance‐approved linkages with other datasets occur. Methods Separate agreements and approval processes govern N3C data contribution and data access. The Linkage Honest Broker (LHB), an independent neutral party (the Regenstrief Institute), ensures data linkages are robust and secure by adding an extra layer of separation between protected health information and clinical data. The LHB's PPRL methods (including algorithms, processes, and governance) match patient records using “deidentified tokens,” which are hashed combinations of identifier fields that define a match across data repositories without using patients' clear‐text identifiers. Results These methods enable three linkage functions: Deduplication, Linking Multiple Datasets, and Cohort Discovery. To date, two external repositories have been cross‐linked. As of March 1, 2023, 43 sites have signed the LHB Agreement; 35 sites have sent tokens generated for 9 528 998 patients. In this initial cohort, the LHB identified 135 037 matches and 68 596 duplicates. Conclusion This large‐scale linkage study using deidentified datasets of varying characteristics established secure methods for protecting the privacy of N3C patient data when linked for research purposes. This technology has potential for use with registries for other diseases and conditions.

The multi-generation systems with simultaneous production of power by renewable energy, in addition to polymer electrolyte membrane electrolyzer and fuel cell (PEMFC-PEMEC) energy storage, have become more and more popular over the past few years. The fresh water provision for PEMECs in such systems is taken into account as one of the main challenges for them, where conventional desalination technologies such as reverse osmosis (RO) and mechanical vapor compression (MVC) impose high electricity consumption and costs. Taking this point into consideration, as a novelty, solar still (ST) desalination is applied as an alternative to RO and MVC for better techno-economic justifiability. The comparison, made for a residential building complex in Hawaii in the US as the case study demonstrated much higher technical and economic benefits when using ST compared with both MVC and RO. The photovoltaic (PV) installed capacity decreased by 11.6 and 7.3 kW compared with MVC and RO, while the size of the electrolyzer declined by 9.44 and 6.13%, and the hydrogen storage tank became 522.1 and 319.3 m3 smaller, respectively. Thanks to the considerable drop in the purchase price of components, the payback period (PBP) dropped by 3.109 years compared with MVC and 2.801 years compared with RO, which is significant. Moreover, the conducted parametric study implied the high technical and economic viability of the system with ST for a wide range of building loads, including high values.