HIGH THROUGHPUT QUANTITATION OF HUMAN NEUTROPHIL RECRUITMENT AND FUNCTIONAL RESPONSES IN AN AIR-BLOOD BARRIER ARRAY.

Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress towards therapeutics. Namely, high throughput therapeutic screening systems typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well Leukocyte recruitment in an Air-Blood Barrier Array (L-ABBA-96) that enables in vivo -like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 (IL-8) and found a dose dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently FDA-approved for severe COVID-19 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

Biceps Pulley Lesions: Diagnostic Accuracy of Nonarthrographic Shoulder MRI and the Value of Various Diagnostic Signs.

BACKGROUND: There is limited data in the literature regarding the role of nonarthrographic MRI for detecting biceps pulley (BP) lesions. PURPOSE: To assess the accuracy of nonarthrographic MRI for detecting BP lesions, and to evaluate the diagnostic value of various MRI signs (superior glenohumeral ligament discontinuity/nonvisibility, long head of biceps (LHB) displacement sign or subluxation/dislocation, LHB tendinopathy, and supraspinatus and subscapularis tendon lesions) in detecting such lesions. STUDY TYPE: Retrospective. POPULATION: 84 patients (32 in BP-lesion group and 52 in BP-intact group-as confirmed by arthroscopy). FIELD STRENGTH/SEQUENCE: 1.5-T, T1-weighted turbo spin echo (TSE), T2-weighted TSE, and proton density-weighted TSE spectral attenuated inversion recovery (SPAIR) sequences. ASSESSMENT: Three radiologists independently reviewed all MRI data for the presence of BP lesions and various MRI signs. The MRI signs and final MRI diagnoses were tested for accuracy regarding detecting BP lesions using arthroscopy results as the reference standard. Furthermore, the inter-reader agreement (IRA) between radiologists was determined. STATISTICAL TESTS: Student's t-tests, Chi-squared, and Fisher's exact tests, and 4-fold table test were used. The IRA was calculated using Kappa statistics. A P-value <0.05 was considered statistically significant. RESULTS: The sensitivity, specificity, and accuracy of nonarthrographic MRI for detecting BP lesions were 65.6%-78.1%, 90.4%-92.3%, and 81%-86.9%, respectively. The highest accuracy was noticed for the LHB displacement sign (84.5%-86.9%), and the highest sensitivity was registered for the LHB tendinopathy sign (87.5%). Furthermore, the highest specificity was observed for the LHB displacement sign and LHB subluxation/dislocation sign (98.1%-100%). The IRA regarding final MRI diagnosis and MRI signs of BP lesions was good to very good (κ = 0.76-0.98). DATA CONCLUSION: Nonarthrographic shoulder MRI may show good diagnostic accuracy for detecting BP lesions. The LHB displacement sign could serve as the most accurate and specific sign for diagnosis of BP lesions. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Antibiotic Exposure Concurrently with Anti-PD1 Blockade Therapy Reduces Overall Survival in Patients with Child-Pugh Class A Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with a poor prognosis. Treatment with immune checkpoint inhibitors (ICIs) has improved overall survival in patients with HCC. However, not all patients benefit from the treatment. In this study, 59 patients with HCC were enrolled from two medical centers in Saudi Arabia, with 34% using antibiotics concurrently with their Nivolumab (anti-PD1 blockade). The impact of antibiotic use on the clinical outcomes of patients with HCC undergoing treatment with anti-PD1 blockade was examined. The patients' overall survival (OS) was 5 months (95% CI: 3.2, 6.7) compared to 10 months (95% CI: 0, 22.2) (p = 0.08). Notably, patients with Child-Pugh A cirrhosis receiving anti-PD1 blockade treatment without concurrent antibiotic use showed a significantly longer median OS reaching 22 months (95% CI: 6.5, 37.4) compared to those who were given antibiotics with a median OS of 6 months (95% CI: 2.7, 9.2) (p = 0.02). This difference in overall survival was particularly found in Child-Pugh class A patients receiving anti-PD1 blockade. These findings suggest that antibiotic use may negatively affect survival outcomes in HCC patients undergoing anti-PD1 blockade, potentially due to antibiotic-induced alterations to the gut microbiome impacting the anti-PD1 blockade response. This study suggests the need for careful consideration when prescribing antibiotics to patients with HCC receiving anti-PD1 blockade.

Characteristics of chest pain among children presenting to the pediatric emergency department.

Chest pain in pediatric patients is a common concern in pediatric emergency departments (ED). In most cases, benign conditions are related to noncardiac causes, and only a minority of the cases are caused by heart disease. This research aimed to evaluate the causes and characteristics of chest pain among children in a pediatric emergency department. This retrospective study evaluated children younger than 14 years of age who presented to the emergency department of a general pediatric hospital in the Eastern area of Saudi Arabia with non-traumatic chest pain between 2017 and 2022. The data included socioeconomic information, physical examination findings, and the results of basic investigations, such as chest X-ray and electrocardiogram. The Chi-square test was performed to compare various etiologies, with a 5% significant level. The study evaluated 310 patients with a mean age of 9.1±2.7 years. The majority of children presenting with chest pain had normal physical examinations, except 3.3% who showed respiratory and cardiac findings. The diagnostic tests indicated pneumonia in 2.9% and arrhythmia in 2.1% of children. Most patients were discharged with a diagnosis of idiopathic or muscular chest pain. The majority of patients (95%) were treated symptomatically in outpatient settings, with just one patient requiring hospitalization. The most common cause of chest pain prompting a child to visit the ED was idiopathic chest pain. Therefore, this study highlights the significance of obtaining a comprehensive medical history and physical examination to reveal important clues and help avoid unnecessary tests.

Fertility and Pregnancy Outcomes in Patients With Adenomyosis: Is Adenomyosis Synonymous With Infertility?

Adenomyosis is a disease related to the presence of endometrial glands and stromal cells within the uterine myometrium that used to be linked to females that are more than 40 years old and multiparous. Nowadays, females are delaying their pregnancies to their third or fourth decade, and as diagnostic approaches evolve, the disease has become a common problem for females who desire pregnancy. The aim of this study is to identify the physio-pathological factors by which adenomyosis causes infertility and pregnancy complications, as well as the possible results from infertility treatments and the most common pregnancy complications that females with adenomyosis face. A systematic review based on a systematic search from PubMed, Cochrane, and ScienceDirect databases from the past five years was done. Papers with free full text available were subject to the removal of duplicates, screening for relevant titles and abstracts, and a quality assessment to identify the risk of bias (RoB). A total of 10 papers were selected for this study; they include systematic reviews and meta-analyses, cohorts, literature review, and a case-control study. After the review of the data, we conclude that infertility may be due to several factors that impair adequate sperm mobility through the uterus and an impaired implantation of a product. After some fertility treatments were performed, females with adenomyosis had a lower rate of clinical pregnancy. The pregnancy complications such as preterm delivery and hypertension problems related to pregnancy had an increased risk for females with adenomyosis, while for others such as intrauterine fetal death and gestational diabetes, the information is still controversial. The main limitation of this study was the lack of information of physio-pathological-related information probably due to only including data from the past five years.

The Multidisciplinary Management of Perianal Fistulas in Crohn's Disease: A Systematic Review.

Perianal fistulas in Crohn's disease (CD) are often recurring and challenging to treat. This systematic review aimed to evaluate the medical, surgical, and combination treatment options and provide an overview of their efficacy. We performed this systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Our group searched PubMed, Medline, PubMed Central, Google Scholar, and ScienceDirect for articles within the last ten years using different terms and criteria mentioned in detail in the search strategy and eligibility criteria sections. Initially, 739 records were retrieved, out of which we excluded 731 records for various reasons, such as irrelevant titles and abstracts and low scores on quality assessment tools. The evidence for combination (surgical and medical) therapy is superior to that for medical and surgical treatments individually. In contrast, the studies on medical and surgical treatments individually reported varied evidence and efficacy for their respective options.

How Residing in a Long-Term Care Facility Affects Suicidal Risk in Patients With Dementia: A Systematic Review.

This study aims to review the current literature regarding the association between suicide risk in patients aged 65 years or over with dementia residing in long-term care facilities (LTCs). We also evaluate the most common methods of suicide and protective versus risk factors of nursing home (NH) life on suicide behavior in patients with dementia. Following preferred reporting items for systematic reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the relevant free full-text articles found in PubMed, Pub Psych, Cochrane library, and Science Direct up until April 4, 2022. Medical Subject Heading (MeSH) terms and keywords (nursing home, long-term care facility, suicide, self-injurious behavior, dementia), were used to search for full-text randomized clinical trials (RCTs), cross-sectional, case-control, cohort studies, systematic reviews, and studies published in the English language in the last 12 years, focused on human subjects 65 years and older were selected based on predefined eligibility criteria. The search yielded 57,909 articles, of which 12 studies met our inclusion criteria. The articles were subjected to quality appraisal by two reviewers. We used the Newcastle Ottawa scale (NOS) for quality assessment with a mean score of six for 12 observational studies used in this paper. Of the included reports, six were cross-sectional, five were cohort, and one was case-control. Four articles carefully examine the relationship between dementia and suicide, and all confirm the hypothesis that staying in LTCs reduces the risk of suicide in patients with dementia. However, the rest of the articles generally determine a higher risk of suicide in demented patients and describe male gender, non-Hispanic white race, younger age, newly diagnosed with dementia within one-year, mild dementia, comorbidities, depression, previous history of suicidal behavior, low social support and unstable family relationship as the risk factors of suicide in this population. In comparison, extended stay in NHs and other kinds of LTCs, severe dementia with impaired insight, older age, comorbid schizophrenia, physical disability with limitation and more difficulty preparing and executing a suicide plan, positive and robust social relationships, access to professional caregivers and high frequency of visits from relatives marked as the protective factors. Existing research on suicide risk in long-term care facility residents with dementia is limited. However, due to the increase in dementia rates that require people to reside in NHs and on the other hand, considering the multiple risk factors of suicide in the elderly living in such places, the need for a screening system for identifying people at suicide risk and performing preventive therapeutic and behavioral interventions is well felt.

The Role of Leptin in Systemic Lupus Erythematosus: Is It Still a Mystery?

Systemic lupus erythematosus (SLE) is a chronic inflammatory connective tissue disease with varying clinical manifestations. Recent studies have proposed that leptin may be related to SLE development. This study aims to assess current information regarding the relationship between leptin and SLE. A systematic search was done using PubMed, Google Scholar, ScienceDirect, Epistemonikos, and Cochrane Library databases. Studies published in the English language in the last 10 years were selected based on predefined eligibility criteria. The quality of the studies was evaluated using the Newcastle-Ottawa Scale and the Assessment of Multiple Systematic Reviews 2 tool. A total of 12 studies were included in this systematic review. These included systematic reviews/meta-analyses, cross-sectional studies, and case-control studies. Based on the findings of this review, we conclude thatleptin is significantly elevated in SLE patients; however, it does not seem to correlate with disease activity. The exact mechanism of leptin in the pathogenesis of the disease remains unknown and further research is needed regarding this aspect.

Testicular Toxicity of Chloroxylenol in Rats: Biochemical, Pathological and Flow Cytometric Study.

Background: Chloroxylenol (para-chloro-meta-xylenol, PCMX) is claimed to be highly harmful both to humans and the environment. Toxic effects of PCMX on testicular functions are scarcely discussed in the literature. Aim of Study: To study testicular toxic effects of PCMX on male Sprague-Dawley rats. Materials and Methods: Forty animals were randomly distributed into three groups: negative control (G I), vehicle group (G II) and PCMX group (G III). PCMX group was subdivided into three subgroups: GIIIa: received PCMX 100 mg/kg, GIIIb: received PCMX 200 mg/kg and G IIIc: received PCMX 500 mg/kg. Hormonal assay included assessment of serum testosterone and estradiol levels. Histopathological examination of testicular tissue, analysis of cellular viability, necrosis and apoptosis in testicular tissue by flow cytometry, analysis of cellular DNA content and phases of cell cycle analysis by flow cytometry were also performed. Results: Rats in the groups exposed to PCMX (G IIIa, G IIIb and G IIIc) had significantly lower estradiol and testosterone levels in comparison to control groups (G I and GII). Histopathological examination of testicular tissue of PCMX-exposed rats showed irregular crossly sectioned seminiferous tubules with their lumina containing scanty spermatids and spermatozoa. G IIIc animals showed eosinophilic proteinaceous material and vacuolated and necrotic interstitial cells of Leydig. Rats in PCMX-exposed groups (G IIIa, G IIIb and G IIIc) showed significantly lower testicular tissue viability in comparison to control groups (G I and G II). Rats in PCMX-exposed groups (G IIIa, G IIIb and G IIIc) showed significantly lower percentage of cells in the G0/G1 phase in comparison to control groups (G I and G II). Conclusion: Rats exposed to PCMX had significant reduction in testosterone and estradiol levels with marked histopathological alterations affecting testicular tissues. These effects are dose-dependent.

A Systematic Review Comparing Digital Subtraction Angiogram With Magnetic Resonance Angiogram Studies in Demonstrating the Angioarchitecture of Cerebral Arteriovenous Malformations.

In brain arteriovenous malformations (AVMs), there is mismatched communication between arteries and veins, causing a nidal bed between them. This systematic review explores whether a magnetic resonance angiogram (MRA) can be used as a diagnostic imaging tool instead of a digital subtraction angiogram (DSA). Utilizing PubMed, Cochrane, and Google Scholar, as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for article selection, a literature search was conducted over the past five years. Eleven studies were included, with a majority of the articles suggesting a potential for consideration. Arterial spin labeling (ASL) versus time-of-flight (TOF) scans was a comparison study, in addition to the study on pseudo-continuous arterial spin labeling (pc-ASL), which proved its high sensitivity in comparison with DSA scans. Other studies included quantitative magnetic resonance angiogram (Q-MRA) measuring the blood flow and susceptibility weighted imaging (SWI) modality. Although promising, digital subtraction angiogram (DSA) scans have diagnostic superiority. In addition, articles discussed follow-up magnetic resonance angiogram (MRA) scans after surgery. Overall, digital subtraction angiogram remains the gold standard due to its superior spatial resolution and hemodynamic properties; these are the key limitations of magnetic resonance studies. MRA has demonstrated its ability to reproduce high-quality diagnostic images for arteriovenous malformation (AVM) angioarchitecture; however, coupled with their limitations, not many studies with large sample sizes over longer periods have been conducted, and we urge more research into it.

Contamination Assessment of Mangrove Ecosystems in the Red Sea Coast by Polycyclic Aromatic Hydrocarbons.

Mangroves are known as a naturally based solution for climate mitigation and adaptation. Mangroves are at a potential risk of degradation by contaminants such as polycyclic aromatic hydrocarbons (PAHs). In this study, sixteen priority PAHs were analyzed and characterized in forty samples of mangrove seawater and mangrove sediments collected from two coastal areas (i.e., Sharm and Khor Rabigh) along the Red Sea Coast of Rabigh city in August 2013. We found that the average concentration of total PAH in mangrove sediments in the Sharam area (22.09 ng/kg) was higher than that in the Alkhor area (6.51 ng/kg). However, the average concentration of the total PAH in the mangrove seawater in the Alkhor area (9.19 ng/L) was double that in the Sharam area (4.33 ng/L). Phenanthrene and pyrene were the major components in both the mangrove seawater and sediment in all the investigated areas. We observed that the abundance of PAHs with 2-3 aromatic rings was dominant in sediment samples collected from both study areas. This abundance was also observed in seawater from the Sharam area. However, seawater samples from the Alkhor area had abundant PAHs with four aromatic rings. The majority of PAHs in sediment samples of both study areas originated from petrogenic sources, whereas the majority of PAHs in seawater samples originated from pyrogenic sources.

The Spectrum of Postoperative Complications and Outcomes After Pancreaticoduodenectomy: A Retrospective Outlook From a Developing Country.

Background Pancreaticoduodenectomy is an extremely complex surgical procedure that mandates aggressive postoperative management. Unfortunately, in developing countries, the limited resources and poor postoperative care lead to multiple complications and abysmal outcomes. Therefore, our study aimed to evaluate the spectrum of postoperative complications and outcomes among patients undergoing pancreaticoduodenectomy. Methods This retrospective study involved a total of 97 patients who underwent pancreaticoduodenectomy for ampullary, periampullary, or pancreatic tumors. Patients with advanced metastasis and unresectable tumors were excluded from the study. Patients were studied for various parameters including the demographic details, postoperative outcomes, characteristics of the tumor, and postoperative complications. Results Out of 97 patients, 59 (60.8%) patients were males. The mean age of the study participants was 53.43 ± 17.89 years. Jaundice and abdominal pain were the most common presenting symptoms among the study participants. Of the 97 patients, 58 (59.8%) had malignant tumors. A total of 49 patients developed various postoperative complications including surgical site infections (10.3%), anastomosis leakage (9.27%), pancreatic fistula (9.27%), cholangitis (7.2%), and biliary leakage (4.1%). A total of 29 (29.9%) patients expired due to postoperative complications. Conclusions Surgical site infections, anastomosis leakage, pancreatic fistula, cholangitis, and biliary leakage are common but preventable postoperative complications after pancreaticoduodenectomy. These lead to morbidity and mortality, especially in the setting of a resource-deprived developing country. Aggressive postoperative management, improved surgical technique, better intraoperative hemostasis management, and a multi-disciplinary approach for the management of such patients can help in preventing postoperative complications and improving the postoperative outcomes.

The impact of Rumex vesicarius seed water extracts on mice fertility.

Rumex vesicarius (RV) is an edible wild annual plant, and it is reported that it contains a good source of minerals, protein, and ascorbic acid. Several studies have indicated the anti-liver damage, anticancer, antimicrobial, and antioxidant properties of the RV plant. There are currently no reports regarding the effect of RV on fertility. Therefore, this study focuses on the impact of RV water seed extracts on mice fertility. RV plants were collected, and water seed extracts were prepared; 50 mg/kg body weight (BW) of this was then injected into the mice (male and female) using an oral feeding tube 5 days before mating (group I) or during caging of the females with the males for 1 week to detect their fertility rate. In the different female groups, no significant difference between their BW and their newborn's BW in the treated and control groups was found. Female fertility, pregnancy, and offspring rates showed some variation within each female group and between the different female groups. In comparing the fertility and offspring rate between the different groups, there was a significant difference (P < 0.05) between groups I and III females and between groups I and IV females, while the other groups showed no significant differences. In contrast, the other groups showed no significant differences. Regarding the impact of the water seed extract on males, the BW was approximately the same in control and treated males.

Ectopic Bone Tissue Engineering in Mice Using Human Gingiva or Bone Marrow-Derived Stromal/Progenitor Cells in Scaffold-Hydrogel Constructs.

Three-dimensional (3D) spheroid culture can promote the osteogenic differentiation and bone regeneration capacity of mesenchymal stromal cells (MSC). Gingiva-derived progenitor cells (GPC) represent a less invasive alternative to bone marrow MSC (BMSC) for clinical applications. The aim of this study was to test the in vivo bone forming potential of human GPC and BMSC cultured as 3D spheroids or dissociated cells (2D). 2D and 3D cells encapsulated in constructs of human platelet lysate hydrogels (HPLG) and 3D-printed poly (L-lactide-co-trimethylene carbonate) scaffolds (HPLG-PLATMC) were implanted subcutaneously in nude mice; cell-free HPLG-PLATMC constructs served as a control. Mineralization was assessed using micro-computed tomography (µCT), histology, scanning electron microscopy (SEM) and in situ hybridization (ISH). After 4-8 weeks, µCT revealed greater mineralization in 3D-BMSC vs. 2D-BMSC and 3D-GPC (p < 0.05), and a similar trend in 2D-GPC vs. 2D-BMSC (p > 0.05). After 8 weeks, greater mineralization was observed in cell-free constructs vs. all 2D- and 3D-cell groups (p < 0.05). Histology and SEM revealed an irregular but similar mineralization pattern in all groups. ISH revealed similar numbers of 2D and 3D BMSC/GPC within and/or surrounding the mineralized areas. In summary, spheroid culture promoted ectopic mineralization in constructs of BMSC, while constructs of dissociated GPC and BMSC performed similarly. The combination of HPLG and PLATMC represents a promising scaffold for bone tissue engineering applications.

Catalyst-Free Crosslinking Modification of Nata-de-Coco-Based Bacterial Cellulose Nanofibres Using Citric Acid for Biomedical Applications.

Bacterial cellulose (BC) has gained attention among researchers in materials science and bio-medicine due to its fascinating properties. However, BC's fibre collapse phenomenon (i.e., its inability to reabsorb water after dehydration) is one of the drawbacks that limit its potential. To overcome this, a catalyst-free thermal crosslinking reaction was employed to modify BC using citric acid (CA) without compromising its biocompatibility. FTIR, XRD, SEM/EDX, TGA, and tensile analysis were carried out to evaluate the properties of the modified BC (MBC). The results confirm the fibre crosslinking phenomenon and the improvement of some properties that could be advantageous for various applications. The modified nanofibre displayed an improved crystallinity and thermal stability with increased water absorption/swelling and tensile modulus. The MBC reported here can be used for wound dressings and tissue scaffolding.

Understanding of how the properties of medical grade lactide based copolymer scaffolds influence adipose tissue regeneration: Sterilization and a systematic in vitro assessment.

Aliphatic polyesters are the synthetic polymers most commonly used in the development of resorbable medical implants/devices. Various three-dimensional (3D) scaffolds have been fabricated from these polymers and used in adipose tissue engineering. However, their systematic evaluation altogether lacks, which makes it difficult to select a suitable degradable polymer to design 3D resorbable implants and/or devices able to effectively mimic the properties of adipose tissue. Additionally, the impact of sterilization methods on the medical devices, if any, must be taken into account. We evaluate and compare five different medical-grade resorbable polyesters with l-lactide content ranging from 50 to 100 mol% and exhibiting different physiochemical properties depending on the comonomer (d-lactide, ε-caprolactone, glycolide, and trimethylene carbonate). The salt-leaching technique was used to prepare 3D microporous scaffolds. A comprehensive assessment of physical, chemical, and mechanical properties of the scaffolds was carried out in PBS at 37 °C. The cell-material interactions and the ability of the scaffolds to promote adipogenesis of human adipose tissue-derived stem cells were assessed in vitro. The diverse physical and mechanical properties of the scaffolds, due to the different composition of the copolymers, influenced human adipose tissue-derived stem cells proliferation and differentiation. Scaffolds made from polymers which were above their glass transition temperature and with low degree of crystallinity showed better proliferation and adipogenic differentiation of stem cells. The effect of sterilization techniques (electron beam and ethylene oxide) on the polymer properties was also evaluated. Results showed that scaffolds sterilized with the ethylene oxide method better retained their physical and chemical properties. Overall, the presented research provides (i) a detailed understanding to select a degradable polymer that has relevant properties to augment adipose tissue regeneration and can be further used to fabricate medical devices/implants; (ii) directions to prefer a sterilization method that does not change polymer properties.

Vitamin D3-loaded electrospun cellulose acetate/polycaprolactone nanofibers: Characterization, in-vitro drug release and cytotoxicity studies.

Vitamin D deficiency is now a global health problem; despite several drug delivery systems for carrying vitamin D due to low bioavailability and loss bioactivity. Developing a new drug delivery system to deliver vitamin D3 is a strong incentive in the current study. Hence, an implantable drug delivery system (IDDS) was developed from the electrospun cellulose acetate (CA) and ε-polycaprolactone (PCL) nanofibrous membrane, in which the core of implants consists of vitamin D3-loaded CA nanofiber (CAVD) and enclosed in a thin layer of the PCL membrane (CAVD/PCL). CA nanofibrous mat loaded with vitamin D3 at the concentrations of 6, 12, and 20% (w/w) of vitamin D3 were produced using electrospinning. The smooth and bead-free fibers with diameters ranged from 324 to 428 nm were obtained. The fiber diameters increased with an increase in vitamin D3 content. The controlled drug release profile was observed over 30-days, which fit with the zero-order model (R2 > 0.96) in the first stage. The mechanical properties of IDDS were improved. Young's modulus and tensile strength of CAVD/PCL (dry) were161 ± 14 and 13.07 ± 2.5 MPa, respectively. CA and PCL nanofibers are non-cytotoxic based on the results of the in-vitro cytotoxicity studies. This study can further broaden in-vivo study and provide a reference for developing a new IDDS to carry vitamin D3 in the future.

The validity, reliability, and reviewer acceptance of VI-RADS in assessing muscle invasion by bladder cancer: a multicenter prospective study.

OBJECTIVE: To assess diagnostic validity and reliability of VI-RADS in predicting muscle invasion by bladder cancer (BCa) and evaluate reviewer acceptance of VI-RADS for clinical routine. METHODS: A prospective multicenter study enrolled 331 patients with suspected/untreated BCa who underwent preoperative multiparametric MRI examination (mp-MRI) of the urinary bladder. Four experienced radiologists independently evaluated all mp-MRI using VI-RADS. The diagnostic validity of VI-RADS for predicting muscle invasion by BCa was calculated using histopathology of the first transurethral resection bladder tumor (TURBT) and second TURBT as the reference standards. The kappa statistics (κ) were applied to assess the interreader agreement (IRA). Reviewer acceptance was evaluated with questionnaires. RESULTS: The risk of muscle invasion in VI-RADS 2, 3, 4, and 5 after the first and second TURBT was 21.8%, 45.8%, 69.6%, and 96.4% and 24.4%, 58.3%, 87%, and 99.2%, respectively. The overall diagnostic validity of VI-RADS was high. The optimal cut-off value for predicting muscle invasion after first TURBT was > VI-RADS 3 (sensitivity = 84.1% and specificity = 92.3%), and after second TURBT was > VI-RADS 2 (sensitivity = 89.9% and specificity = 90.1%). VI-RADS categorization showed a very good IRA (κ = 0.93). Reviewers fully agreed with the statement, "The application of structured reporting of bladder tumor should be encouraged" (score = 20). CONCLUSIONS: VI-RADS showed high diagnostic validity and reliability for predicting muscle invasion by BCa, especially VI-RADS 4 and 5. However, VI-RADS 2 and 3 require further modifications to enhance their diagnostic validity. VI-RADS is highly encouraged to be used in daily practice. KEY POINTS: • VI-RADS showed high diagnostic validity and reliability in predicting BCa muscle invasion, especially VI-RADS 4 and 5. • In VI-RADS 2 and 3, we observed a notable percentage of BCa with muscle invasion and this would require further modifications to enhance the diagnostic validity for these scores. • Overall VI-RADS is well-accepted by radiologists who recommend it for daily practice.

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

Firefighter exposures to organic and inorganic gas emissions in emergency residential and industrial fires.

The gas emissions generated from fires could cause mortalities and diseases in firefighters. Gas emissions from fire contain a mixture of a wide range of organic and inorganic gases, depending on several elements that are not currently known. In this study, firefighters were equipped with portable gas detectors to measure selected organic and inorganic gases in 26 emergency fire incidents. The fire incidents were categorized as industrial or residential based on their source. The exposure of firefighters to volatile organic compounds (VOCs) in residential fires was double that in industrial fires. This is probably due to the contents of the houses, as more VOCs are released from textiles and furniture. The concentration of toluene, which is widely used in cosmetics and paints in housing, was fifteen-fold higher in residential fires than industrial fires. The exposure of firefighters to inorganic gases was much higher in industrial fires than residential fires. The concentration of hydrogen chloride, which is generated from the combustion of chlorinated plastics, such as industrial pipes and cables, in industrial fires was 18-fold higher than that in residential fires. Additionally, in this study, we found that the concentration of VOCs that poses cancer and non-cancer health risk to firefighters increases in residential fire incidents to almost three times that in industrial fire incidents. Hydrogen sulfide and sulfur dioxide concentrations were higher in industrial fire incidents than in residential fire incidents. The level of hydrogen sulfide and sulfur dioxide were 19-fold and 8-fold higher, respectively, in industrial fire incidents than in residential fire incidents. This study reveals that gas emissions vary widely between industrial and residential fires.