Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications.

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS: Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS: The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION: Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.

Generic orphan drug substitution: a critical analysis of global practices and Saudi Arabia's perspective.

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

Novel sustainable steel fiber reinforced preplaced aggregate concrete incorporating Portland limestone cement.

This study proposes a novel approach by adding Portland limestone cement (PLC) to preplaced aggregate steel fiber reinforced concrete (PASFRC) to create a sustainable concrete that minimizes CO2 emissions and cement manufacturing energy usage. The method involves injected a flowable grout after premixing and preplacing steel-fibers and aggregates in the formwork. This study evaluates the mechanical properties of a novel sustainable concrete that uses PLC and steel fibers. To achieve the intended objective, long and short end-hooked steel fibers of 1%, 2%, 3%, and 6% were incorporated in PASFRC. Also, Analysis of variance (ANOVA) was used to examine the data. Results indicated that PLC and higher fiber doses increased the mechanical properties of PAC. At 90 days, PASFRC mixtures containing 6% long steel fibers demonstrated superior compressive, tensile, and flexural strengths, registering the highest values of 49.8 MPa, 7.7 MPa, and 10.9 MPa, respectively and differed by 188%, 166%, and 290%, respectively from fiberless PAC. The study confirmed the suitability and effectiveness of using PLC with steel fibers in PAC which significantly improved the mechanical properties of PASFRC. This was verified through analytical analysis and new empirical equations were proposed to predict the mechanical properties of PASFRC.

Comparative effectiveness and cost evaluation of Risankizumab and Adalimumab in the management of psoriasis: a real-world study in Saudi Arabia.

BACKGROUND: Psoriasis, an immune-mediated chronic inflammatory disease primarily affecting skin and joints, has varying prevalence rates globally. It manifests in five types, with chronic plaque psoriasis being the most common. Treatment, which has no definitive cure, aims for complete resolution of skin symptoms and depends on disease extent, severity, and impact on patients' lives. Biologics are an emerging treatment for psoriasis, targeting specific inflammatory pathways for potentially safer, more effective outcomes. However, these come with significant costs, necessitating more research to ensure value for money. This study aimed to compare the effectiveness of Risankizumab versus Adalimumab, the most commonly utilized biologic for managing psoriasis in Saudi Arabia. METHODS: This study retrospectively compared the effectiveness and direct medical cost of Risankizumab and Adalimumab in treating chronic plaque psoriasis in adults from two Saudi Arabian healthcare centers. The Psoriasis Area and Severity Index (PASI) and body surface area (BSA) were used to assess treatment effectiveness, with patient data sourced from electronic medical records. Multiple regression analysis was performed to examine various factors affecting treatment outcomes. An economic evaluation was conducted to examine the cost-effectiveness of the two drugs, considering four scenarios with varying dosage patterns and costs. Analysis was performed from the perspective of public healthcare payers and considered all utilized health services. RESULTS: The data for 70 patients were analyzed, with comparable baseline characteristics between groups. While Risankizumab led to a greater reduction in PASI scores and BSA affected, these results were not statistically significant. The annual treatment cost for Risankizumab was higher than Adalimumab. Various scenarios were studied, considering real acquisition costs, double dosing for Adalimumab, and the use of biosimilars. A scenario assuming double dosing for Adalimumab and a 40% discount for Risankizumab demonstrated both cost and efficacy advantages in 71.25% of cases. CONCLUSIONS: This study compared the effectiveness and cost of Risankizumab and Adalimumab for treating chronic plaque psoriasis in Saudi Arabian hospitals. Although Risankizumab showed a greater reduction in symptoms, the difference was not statistically significant. However, under certain scenarios, Risankizumab demonstrated cost and efficacy advantages. These findings may influence treatment decisions for psoriasis, but further research is needed.

Vertical Marginal Discrepancy of a Monolithic Zirconia Crown with Different Cement Spaces.

The long-term clinical success of indirect restorations highly depends on their marginal integrity. The cement space is an element that might affect the marginal integrity, but it can be altered during the configuring of the computer-assisted designing/computer-aided manufacturing (CAD-CAM) restoration. However, there is controversy in the literature regarding the effect of the cement space on the precision of zirconia crown marginal adaptation. The aim of this study was to measure the vertical marginal discrepancies between different cement thickness settings for CAD-CAM monolithic zirconia restorations. Material and Methods. An artificial mandibular right molar tooth mounted on a typodont was prepared for a zirconia crown using the standard method. The study sample consisted of 30 zirconia crowns (Zenostar Zr Translucent Zirconia, Weiland Dental, Germany) milled using an (iMes-iCore) milling machine. Each group of 10 crowns was designed with 30-50 and 70 µm spacer thicknesses. The vertical marginal adaptation at the center of the four different planes (mesial, distal, buccal, and palatal) was measured under a microscope at 40x magnification. A one-way analysis of variance test was used for statistical analysis. Results. The mean of Group 30 was 27.45; of Group 50 was 22.22; and of Group 70 was 22.90. There was no statistically significant difference between the groups (p ≥ 0.5). Conclusions. The increase in the cement space up to 70 µm did not influence the vertical marginal adaptation of the monolithic zirconia crowns.

The Management of Intussusception: A Systematic Review.

Intussusception (ISN) is a dangerous condition where a portion of the intestine slides into an adjacent area of the intestine. This telescoping motion frequently prevents liquids or food from flowing through. Developing management guidelines for ileocolic (IC) intussusception was the aim of this systematic study. Data sources were PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, and Embase databases. Our review investigated English-language articles (from 2010 to 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall, there were 15 articles. Surveys and analyses of national databases were the most widely used methods (n=15). The search identified 561 studies; 15 were eligible for inclusion in the analysis. Further understanding of the management of intussusception may help improve evaluation and management in the future. The use of preventive antibiotics does not reduce problems following radiologic reduction. When clinically appropriate, repeated attempts at enema reduction may be made. After the enema reduction of ileocolic intussusception, patients can be safely watched in the emergency room (ER), thereby avoiding hospitalization. Success rates for laparoscopic reduction are high. When it comes to intussusception in children who are hemodynamically stable and do not have a serious illness, there is no need for pre-reduction antibiotics. Prioritizing nonoperative outpatient (OP) therapy is recommended as the primary approach, with the utilization of minimally invasive procedures to avoid the necessity for laparotomy. The management of colonic intussusception involves complete removal in one piece, while enteric intussusception can be addressed through reduction followed by resection. A targeted approach is recommended, recognizing the intermediate forms of intussusception that may exist between the colonic and enteric types. It is essential to note that the prevailing treatment for adult intussusception remains to be surgical intervention.

DAPTA, a C-C Chemokine Receptor 5 (CCR5), Leads to the Downregulation of Notch/NF-κB Signaling and Proinflammatory Mediators in CD40+ Cells in Experimental Autoimmune Encephalomyelitis Model in SJL/J Mice.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by motor deficits, cognitive impairment, fatigue, pain, and sensory and visual dysfunction. CD40, highly expressed in B cells, plays a significant role in MS pathogenesis. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS has been well established, as well as its relevance in MS patients. This study aimed to evaluate the therapeutic potential of DAPTA, a selective C-C chemokine receptor 5 (CCR5) antagonist in the murine model of MS, and to expand the knowledge of its mechanism of action. Following the induction of EAE, DAPTA was administrated (0.01 mg/kg, i.p.) daily from day 14 to day 42. We investigated the effects of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α in CD40+ spleen B cells using flow cytometry. Furthermore, we also analyzed the effect of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α mRNA expression levels using qRT-PCR in brain tissue. EAE mice treated with DAPTA showed substantial reductions in NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α but an increase in the IκBα of CD40+ B lymphocytes. Moreover, EAE mice treated with DAPTA displayed decreased NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α and but showed increased IκBα mRNA expression levels. This study showed that DAPTA has significant neuroprotective potential in EAE via the downregulation of inflammatory mediators and NF-κB/Notch signaling. Collectively, DAPTA might have potential therapeutic targets for use in MS treatment.

Cost Consequence Analysis of Belimumab versus Standard of Care for the Management of Systemic Lupus Erythematosus in Saudi Arabia: A Retrospective Cohort Study.

BACKGROUND: Belimumab use for the management of systemic lupus erythematosus (SLE) has been limited, in part due to its high acquisition cost relative to the standard of care (SoC) and the uncertainties about its cost-effectiveness. Therefore, the aim of this study was to compare the cost and effectiveness of belimumab versus the SoC alone for the management of SLE using real-world data from the perspective of public healthcare payers in Saudi Arabia. METHODS: Data were retrieved from a national prospective cohort of SLE, Saudi Arabia. Adult SLE patients (≥18 yrs.) treated with belimumab plus the SoC or the SoC alone for at least six months were recruited. The effectiveness was measured using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Unit costs for health services and prescription drugs were retrieved from the Saudi ministry of health. Nonparametric bootstrapping with inverse probability weighting was conducted to generate the 95% confidence limits for the cost and effectiveness. RESULTS: A total of 15 patients on belimumab plus the SoC and 41 patients on the SoC alone met the inclusion criteria and were included in the analysis. The majority of patients were females (91.07%) with a mean age of 38 years. The mean difference in cost and SLEDAI-2K score reduction between belimumab versus the SoC were USD 5303.16 [95% CI: USD 2735.61-USD 7802.52] and 3.378 [95% CI: 1.769-6.831], respectively. Belimumab demonstrated better effectiveness but higher cost in 96% of the bootstrap cost-effectiveness distributions. CONCLUSION: Future studies should use more robust research designs and a larger sample size to confirm the findings of this study.

The impact of Hydroxyurea on the rates of Vaso-occlusive crises in patients with sickle cell disease in Saudi Arabia: a single-center study.

BACKGROUND: Vaso-occlusive crises (VOCs) are acute and common painful complication of sickle cell disease (SCD), and are the main reason behind the frequent emergency department visits among SCD patients. Hydroxyurea (HU) is an old and commonly used medication that demonstrated its effectiveness in reducing the risk of VOCs and the incidence of hospitalization. Although multiple studies have examined the impact of HU on the rates of VOCs, few have explored its effectiveness among SCD patients in Saudi Arabia. METHODS: This was a single-center retrospective cohort study in which the electronic medical records of patients with SCD who have not had any previous exposure to HU prior to the initiation of HU treatment for ≥12 months were recruited. Paired t-test was conducted to examine the difference in the rates of VOCs, and levels of hemoglobin (Hgb), hematocrit (HCT), and platelet counts (PLT Ct) prior to the initiation of HU therapy and 12 months later. Multiple linear regression was conducted to examine whether age, gender, use of opioid analgesics, Hgb, HCT, and PLT Ct levels predict higher or lower rates of VOCs. RESULTS: One hundred and fifty-six patients met the inclusion criteria and were included in the analysis. About 51% of the patients were males, and their mean age was 12.69 years. The mean HU dosage was 16.52 mg/kg/day, and the mean reduction in the rate of VOCs was 1.36 events per patient per year (95% CI [1.03-1.70], p < 0.0001) after the initiation of HU. Females were more likely to have greater reduction in the rates of VOCs in comparison to their male counterparts (ß-estimate = 12.85, 95% CI [0.759-24.93], p = 0.0374). CONCLUSION: The use of HU results in a significant reduction in the rates of VOCs and emergency department visits. Future studies with robust research designs should be conducted to further examine the impact of HU on VOCs, hospitalization, and length of stay as well as compare HU to other newly approved medications for SCD, such as crizanlizumab.

A study on vaginitis among pregnant and non-pregnant females in Alexandria, Egypt: An unexpected high rate of mixed vaginal infection.

Background: Many infectious and noninfectious triggers lead to inflammation of the vagina. Aim: We investigated the prevalence of causative vaginitis microorganisms in 516 pregnant and nonpregnant female volunteers. Vaginal samples were examined microscopically, cultured and tested for different pathogens. Results: Of the participants, 310 (60.1%) were pregnant, whereas 206 (39.9%) were nonpregnant. Using Amsel's criteria and Nugent's scores, bacterial vaginosis (BV) was diagnosed in 59.1%, and the prevalence of vulvovaginal candidiasis (VVC) was 50.2% in the population. Candida infections were significantly higher in nonpregnant females (p value ≤ 0.01), and 24% of females had mixed infections. The most common mixed infection was BV and Candida spp., detected in 21% of the cases. Conclusions: Bacterial vaginosis is the most common cause of vaginitis. We observed that 24% of females experienced mixed infections, and Candida albicans was the most common fungal species causing VVC. Trichomonas vaginalis prevalence was underestimated using wet mounts.

Evaluation of clinical trials for natural products used in diabetes: An evidence-based systemic literature review.

BACKGROUND RELEVANCE: A plethora of literature is available regarding the clinical trials for natural products however; no information is available for critical assessments of the quality of these clinical trials. AIM OF STUDY: This is a first time report to critically evaluate the efficacy, safety and large scale applications of up-to-date clinical trials for diabetes, based on the three scales of Jadad, Delphi, and Cochrane. METHODOLOGY: An in-depth and extensive literature review was performed using various databases, journals, and books. The keywords searched included, "clinical trials," "clinical trial in diabetes," "diabetes," "natural products in diabetes," "ethnopharmacological relevance of natural products in diabetes," etc. RESULTS: Based on eligibility criteria, 16 plants with 74 clinical trials were found and evaluated. Major drawbacks observed were; "non-randomization and blindness of the studies," "non-blindness of patients/healthcare/outcome assessors," "lack of patient compliance and co-intervention reports," "missing information regarding drop-out/withdrawal procedures," and "inappropriate baseline characteristics." Principal component analysis and Pearson correlation revealed four components with %variability; PC1: 23.12, PC2: 15.83, PC3: 13.11, and PC4: 11.38 (P ≤ .000). According to descriptive statistics, "non-blinding of outcome assessors" was the major drawback (82%) whereas, "not mentioning the timing of outcome assessment" was observed lowest (6.8%). An in-house quality grading (scale 0-24) classified these clinical trials as; poor (67.6%), acceptable (19.9%), and good quality trials (13.5%). CONCLUSION: Proper measures in terms of more strict regulations with pharmacovigilance of plants are utmost needed in order to achieve quality compliance of clinical trials.