Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome.

BACKGROUND: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear. METHODS: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome. RESULTS: Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection. CONCLUSIONS: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

Pathogenic mechanisms in the evolution of food allergy.

The early development of the neonatal immune system is profoundly influenced by exposure to dietary and microbial antigens, which shapes mucosal tolerance. Successful oral tolerance induction is crucially dependent on microbially imprinted immune cells, most notably the RORγt+ regulatory T (Treg) and antigen presenting cells and is essential for preventing food allergy (FA). The development of FA can be envisioned to result from disruptions at key checkpoints (CKPTs) that govern oral tolerance induction. These include gut epithelial sensory and effector circuits that when dysregulated promote pro-allergic gut dysbiosis. They also include microbially imprinted immune regulatory circuits that are disrupted by dysbiosis and pro-allergic immune responses unleashed by the dysregulation of the aforementioned cascades. Understanding these checkpoints is essential for developing therapeutic strategies to restore immune homeostasis in FA.

Assessment of Parental Risk Factors Involved in Orofacial Clefts in Hail, Saudi Arabia: A Retrospective Cohort Study.

Background Orofacial clefts are congenital anomalies affecting the development of the oral and facial structures, influenced by genetic and environmental factors. The prevalence of orofacial clefts varies globally, necessitating region-specific studies to understand contributing factors. Orofacial clefts are among the most common congenital defects affecting the head and neck, underscoring the importance of investigating paternal and maternal influences on their development to enhance awareness and understanding of potential contributing factors. Therefore, this research aimed to investigate parental risk factors contributing to the development of orofacial clefts.  Methods A retrospective cohort study was conducted at the Oral and Maxillofacial Department of King Khaled Hospital, Hail, Saudi Arabia, involving 40 parents of children born between 2019 and 2023 with orofacial clefts. Data collection included interviewer-administered questionnaires with parents addressing demographic information, pregnancy details, parental medical history, and postoperative outcomes. Statistical analysis utilized descriptive statistics, chi-square tests, Fisher's exact test, and linear regression, with significance defined as p<0.05. Results The study had a gender distribution of 19 males (47.5%) and 21 females (52.5%) among orofacial cleft cases (p<0.75), with cleft palate (13 cases, 32.5%) and cleft lip (11 cases, 27.5%) being the most prevalent anomalies (p<0.05). Maternal supplementation rates were high, with 34 mothers (85%, p<0.05) taking folic acid and 36 mothers (90%, p<0.05) taking iron, yet orofacial clefts incidence persisted. Paternal risk factors such as tobacco use were reported by 19 fathers (47.5%, p<0.05), and familial history of orofacial clefts was noted in nine cases (22.5%, p<0.05). Postoperative outcomes indicated varying levels of functional recovery and satisfaction. Conclusion This study explored the complex origins of orofacial clefts, emphasizing genetic and environmental influences. The findings suggest a potential paternal risk factor. The study highlights the need for further investigation into genetic mechanisms and the development of effective prevention strategies.

Immunological biomarkers associated with survival in a cohort of Argentinian patients with common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is the most common symptomatic syndrome among inborn errors of immunity. Although several aspects of CVID immunopathology have been elucidated, predictive factors for mortality are incompletely defined. A genetic cause can be identified only in approximately 30% of patients. Objective: We sought to develop a mortality predictive score on the basis of the immunophenotypes and genotypes of patients with CVID. Methods: Twenty-one patients diagnosed with CVID in Córdoba, Argentina, were analyzed for clinical and laboratory data. Immunophenotyping was done by flow cytometry. CVID-associated mutations were identified by whole-exome sequencing. Results: Alive (15) and deceased (6) patients were compared. Univariate analysis showed significant differences in CD4+ T cells (P = .002), natural killer (NK) cells (P = .001), and memory switched B cells (P = .001) between groups. Logistic regression analysis showed a negative correlation between CD4+, NK, and memory switched B-cell counts and probability of survival over a 10-year period (CD4+ T cells: odds ratio [OR], 1.01; 95% CI, 1.001-1.020; NK cells: OR, 1.07; 95% CI, 1.02-1.17; and memory switched B cells: OR, 26.23; 95% CI, 2.06-2651.96). Receiver-operating characteristic curve analysis identified a survival cutoff point for each parameter (CD4+ T cells: 546 cells/mL; AUC, 0.87; sensitivity, 60%; specificity, 100%; memory switched B cells: 0.84 cells/mL; AUC, 0.92; sensitivity, 100%; specificity, 85%; and NK cells: 45 cells/mL; AUC, 0.92; sensitivity, 83%; specificity, 100%). Genetic analysis on 14 (9 female and 5 male) patients from the cohort revealed mutations associated with inborn errors of immunity in 6 patients. Conclusions: A score to predict mortality is proposed on the basis of CD4+ T, NK, and memory switched B-cell counts in patients with CVID.

Satisfaction-Behavior Paradox in Lifestyle Choices: A Cross-Sectional Study of Health Behaviors and Satisfaction Levels in Jazan, Saudi Arabia.

BACKGROUND: Lifestyle choices significantly affect health outcomes in Saudi Arabia, but the relationship between health behaviors and satisfaction is unclear. This study aimed to assess lifestyle choices and associated satisfaction levels among residents in the Jazan region of Saudi Arabia. METHODS: A cross-sectional study was conducted in Jazan, Saudi Arabia, with 3411 participants. Sociodemographic, lifestyle, and satisfaction data were collected using a questionnaire that was completed during interviews. Logistic regression analyses were implemented to examine the relationships between the study variables and factors related to weight, physical activity, and eating satisfaction. RESULTS: The study found that 38.3% of participants were inactive and 77% rarely ate fruits and vegetables. A total of 47.6% were overweight or obese. Weight (71.12%) and eating (71.59%) satisfaction were high despite these health concerns. The satisfaction-behavior paradox was especially evident in diet. Higher income, physical activity, and healthy eating habits were significantly associated with higher satisfaction (OR = 1.49, 95% CI: 1.15-1.93, p = 0.003 for weight satisfaction, OR = 34.74, 95% CI: 25.42-48.35, p < 0.001 for physical activity satisfaction, and OR = 2.08, 95% CI: 1.67-2.61, p < 0.001 for fruit and vegetable consumption). CONCLUSIONS: Lifestyle behaviors and satisfaction in Jazan, Saudi Arabia, are complex. The satisfaction-behavior paradox, especially in diet, reveals a major gap between perceived and actual health. These findings highlight the need for targeted, culturally sensitive interventions that address behavioral change and perception alignment to improve regional public health.

Awareness and Underlying Factors for Total Knee Arthroplasty Reluctance in Saudi Arabia.

Background Total knee arthroplasty (TKA) is a successful surgical intervention for advanced knee arthritis. The efficacy of TKA in reducing pain and restoring joint function has been well documented. Despite the rewarding outcomes of TKA for knee osteoarthritis patients, their willingness to consider the procedure is limited. Aim This study aimed to assess patients' awareness and knowledge of total knee arthroplasty benefits and complications. Further, the reasons and factors contributing to reluctance among orthopedic patients in Saudi Arabia should be determined. Methods An online, structured, and self-administered questionnaire was used to collect data from adult orthopedic patients of both genders who were reluctant to undergo total knee arthroplasty despite surgeons' recommendations. The online questionnaire link was shared across multiple platforms, orthopedic forums, and healthcare social media channels. Qualitative data were presented as frequencies and percentages, while continuous data were reported as the mean (standard deviation [SD]). The statistical package for the social sciences software program was used for statistical analysis. Results A total of 629 participants were involved. The awareness of the expected benefits score, on a scale from 7 to 35, showed a mean (SD) of 20.9 (5.6). The score of the attitude towards expected complications, on a scale from 5 to 25, had a mean (SD) of 15.2 (3.6). The attitude towards the expected complications showed a significantly higher mean (SD) score in the older group aged >60 years than the younger one aged <40 years (15.7 (4.1) vs. 14.9 (3.5), respectively). Likewise, overweight and obese participants showed a significantly higher mean (SD) expected complications score compared to the healthy and underweight ones (15.4 (3.7) vs. 14.8 (3.5), respectively). The recorded reasons for refusal to undergo TKA were fear of anesthesia complications (317, 50.4%), followed by financial limitations (245, 39.0%), the unavailability of experienced surgeons (232, 36.9%), and fear of unfavorable outcomes (189, 30.0%). Conclusion There was a gap in knowledge and awareness of total knee arthroplasty among orthopedic patients in Saudi Arabia. Perceptions of benefits were inadequate, and there were misconceptions about the expected complications. The level of expected complications was higher among elderly and obese patients. Furthermore, fear of anesthesia complications and unfavorable outcomes, in addition to economic and financial problems, constituted major barriers to undergoing the procedure.

Aetiologies of Ear Infections Among Patients Who Visited King Fahad Hospital in Al-Baha, Saudi Arabia.

Background Ear infections encompass otitis media (OM) which is a significant cause of hearing loss and otitis externa (OE) which may affect the surrounding tissues leading to serious complications. This study reports the common pathogens causing ear infections. Methods Microbiological, clinical, and demographic data of ear-infected patients who visited King Fahad Hospital in Al-Baha, Saudi Arabia, during the period from January 2019 to June 2023 were enrolled in this study. Result  This study enrolled 307 patients aged 1-94 years, with a median age of 40 years (IQR=22-57). Overall, the detectable infection rate was 81.1% (n=249), while 18.9% (n=58) had no identified aetiology. Of all isolates, 178 (58%) were bacterial, while 71 (23.1%) were fungal. Staphylococcus aureus (S. aureus) followed by Pseudomonas aeruginosa (P. aeruginosa), Enterobacteriaceae, andcoagulase-negative Staphylococcus (CoNS) were the main bacterial isolates. Of the total 63 S. aureus isolates, 21 (33%) were methicillin-resistant (MRSA). A cohort of 227 subjects were diagnosed with either OM (n=178; 79.5%), OE (n=46; 20.5%), or both OM and OE (n=3; 1%). Of those with OM, children constituted 89.1% (41/46) as compared to 75.3% (134/178) of adults (p=0.041). The main isolates from OM patients were S. aureus followed by P. aeruginosa and fungi. Of 49 OE patients, 16 (32.7%) had no identified pathogen, while 15 (30.6%) had fungi, and 13 (29.5%) had P. aeruginosa. Conclusions Ear infections in general were mainly bacterial followed by fungal with a considerable proportion of unidentified aetiology. A significant proportion of S. aureus isolates were MRSA. S. aureus followed by P. aeruginosa and fungi were the main causes of OM, while fungi followed by P. aeruginosa were the main causes of OE.

Saudi consensus guidance for the diagnosis and management of inflammatory bowel disease in children and adolescents.

ABSTRACT: The management of inflammatory bowel disease (IBD) in children and adolescents is challenging. Clear evidence-based guidelines are required for this population. This article provides recommendations for managing IBD in Saudi children and adolescents aged 6-19 years, developed by the Saudi Ministry of Health in collaboration with the Saudi Society of Clinical Pharmacy and the Saudi Gastroenterology Association. All 57 guideline statements are based on the most up-to-date information for the diagnosis and management of pediatric IBD.

Study of the Synergistic Influence of Plasma Electrolytic Oxidation and Wet Post-Treatment on the Surface of AA7075.

In this study, we enhanced the corrosion and microbial resistance of aluminum 7075 alloys by applying a thin layer of alumina through plasma electrolytic oxidation (PEO) in an alkali-silicate electrolyte. In addition, the influence of film sealing on coated aluminum alloy 7075 was studied in detail, specifically in oil and water at 100 °C after treatment. The surface and cross-sectional morphology, element composition, and phase composition of the PEO coatings were characterized by using scanning electron microscopy (SEM) assisted with energy-dispersive X-ray spectrometry (EDS) and X-ray diffraction (XRD), respectively. The corrosion resistance of the coating on AA7075 PEO was evaluated before and after post-treatment using hot water and hump oil at 100 °C. This assessment was conducted by using various electrochemical techniques, including open-circuit potential (OCP), linear polarization resistance (LPR), potentiodynamic polarization scan (PD), electrochemical impedance spectroscopy (EIS), and cyclic potentiodynamic scan (CPS). The results showed that the corrosion resistance of the AA7075 alloy was significantly improved after the PEO coating. The AA7075 + SF, among all of the examined alloys, exhibited superior corrosion properties, due to its fat sealing. This is probably due to the formation of a mixed fatty acid layer from oil on the surface of the AA7075 PEO, which synthesizes a hydrophobic layer. Interestingly, the samples treated with PEO showed a great resistance to microbial growth.

Soft tissue sarcoma mimicking an arteriovenous malformation - A case report and review of literature.

INTRODUCTION AND IMPORTANCE: Arteriovenous malformation (AVM) is a rare condition affecting less than 5/10,000 people, with high misdiagnosis due to its heterogeneity, inconsistent nomenclature, and diverse diagnostic criteria. Understanding its prevalence in this age group is crucial for effective treatment. Here we present a case report of a patient with AVM. IRB approval and patient consent were obtained. This study was done based on SCARE criteria. CASE PRESENTATION: A 53-year-old female patient was diagnosed with a right hip vascular mass suggestive of AVM. The patient reported painless swelling on the right hip for five years, initially increasing in size but significantly increasing in the last six months. The patient had no history of trauma, neurological or pelvic symptoms, or constitutional symptoms. An examination of the lower limbs revealed a firm, non-tender mass measuring approximately 15 × 15 cm. A thigh MRI revealed a sizable, well-rounded, lobulated soft tissue mass with a stromal structure and pronounced vascularity, indicative of a soft tissue tumor. CLINICAL DISCUSSION: AVMs misdiagnosis is a significant issue, with 40 % of soft tissue sarcomas still misdiagnosed delaying care and leading to unnecessary measures. A 2015 study found 42.5 % of AMV patients were misdiagnosed, and 71 % were misdiagnosed as hemangiomas. Management involves multidisciplinary approaches, including radiology, sclerotherapy, surgical resection, and chemo/radiotherapy. Sirolimus may improve AVM prognosis. CONCLUSION: Misdiagnosis of AVMs is a significant issue, with 40 % of soft tissue sarcomas still misdiagnosed. Management involves multidisciplinary approaches, including interventional radiology, sclerotherapy, surgical resection, and chemo/radiotherapy.

Estimating Proportion and Barriers of Medication Error Reporting Among Nurses in Hail City, Saudi Arabia: Implications for Improving Patient Safety.

Background: Determining the proportion of nurses reporting medication errors (MEs) and identifying the barriers they perceive in ME reporting are crucial to encourage nurses to actively report MEs. Objective: This study aimed to determine the proportion of nurses experiencing and reporting MEs, perceived barriers to reporting MEs and their association with nurses' sociodemographic and work-related characteristics. Methods: A cross-sectional study was conducted among 350 nurses from June to November 2023. Data about sociodemographic and work-related characteristics, and ME reporting, were collected using a validated self-administered questionnaire. Results: The study found that 34.3% of nurses reported MEs, while 11.1% reported experiencing MEs during their practice. ME reporting was higher proportion among nurses who were older than 40 years (52.1%), males (41.4%), held a master's degree (58.7%), Saudi nationals (37.8%), experienced for more than 10 years (43.1%), working in intensive care units (44.3%), working for 48 hours or more per week (39.7%), working in hospitals with a nurse-to-patient ratio of 1:3 (44.9%) and having a system for incident reporting (37.7%) and with no training on patient safety (44.6%) compared to their counterparts. The rate of experiencing MEs was higher proportion among nurses who were older than 40 years (16.7%), males (17.3%), married (14.8%), Saudi nationals (13.4%), experienced for more than 10 years (15.6%) and with no training on patient safety (15.3%) compared to their counterparts. Lack of knowledge of the person responsible for reporting MEs was the most frequent perceived barrier to ME reporting (66.6%), followed by fears of blame (65.4%). Conclusion: In this study, nurses reported and experienced MEs during their practice. Most nurses perceive the lack of knowledge and fear of blame or disciplinary actions as barriers to reporting. Healthcare administrators should implement educational programs and workshops to increase nurses' awareness of ME reporting.

The Effects of Cataract Surgery on Children's Vision: A Systematic Review.

Background: Five-fifths of all incidents of blindness in Saudi Arabia may be attributed to cataracts. Cataracts are the second major cause of blindness, responsible for 35.5% of cases. Therefore, the purpose of the research was to measure the visual acuity improvement after cataract surgery in children. Materials and Methods: This systematic review followed PRISMA guidelines for reporting systematic reviews. All procedures followed the recommendations of the Cochrane handbook. Studies of varying study designs, both published and unpublished, are included. Retrospective studies with outcomes of pediatric cataract surgery were identified from various databases. Result: After an initial screening, 108 out of 167 items were deemed unsuitable for publication. There were 59 full-text papers assessed for inclusion, and only seven matched the criteria. All the articles included were of a very high standard. Both the duration of therapy and the target population varied widely between the studies. Conclusion: The results indicated that the majority of childhood cataracts are hereditary. Primary posterior capsulectomy and anterior vitrectomy combined with cataract extraction and intra-ocular lens implantation is the treatment of choice for pediatric cataracts. It is recommended that surgery be performed in a properly equipped facility staffed by trained, cooperative personnel and that different procedures be used to enhance post-operative follow-up.

Spinal Accessory Nerve Injury following Spinal Adjustment: Case Report and Literature Review of the Outcome of Accessory Nerve Pathology as Result of Blunt Trauma (Spinal Accessory Nerve Palsy after Spinal Adjustment).

Spinal accessory nerve palsy (SANP) is rare and is commonly presented following iatrogenic injury. Their diagnosis is often missed on initial presentation. Injury following blunt trauma is rare, with few cases reported in literature describing blunt-associated SANP and their treatment and recovery. We present and discuss a case of SANP following an aggressive soft tissue adjustment by an uncertified individual that has been responsive to nonsurgical measures over 18 months. We also reviewed the related literature on similar cases that were presented as result of direct pressure on the nerve from soft tissue manipulation or heavy lifting and their outcome following treatment. Chiropractic is generally a safe complimentary medicine and must only be practiced by trained personnel. We found that blunt-caused SANP injuries should initially be treated conservatively as they are likely to respond and recover unlike when presented following invasive trauma accordingly to what we found in literature.

Gastroesophageal Cancer After Laparoscopic Sleeve Gastrectomy.

Obesity has been linked to many types of cancers, and this association has received much attention. Here, we are reporting the case of a 41-year-old male patient, the second case diagnosed in our hospital with advanced metastatic gastroesophageal cancer eight years after laparoscopic sleeve gastrectomy. Routine preoperative endoscopy for all patients planned for bariatric surgery can play an important role in preoperative surgery selection, detection of abnormal pathology/lesions, as well as in postoperative follow-up/esophagogastroduodenoscopy surveillance plans, especially for patients identified as high-risk to develop cancer.

Satisfaction Rate After Laser Correction of Presbyopia (Presbyond) Among Patients Aged 40 Years and Older in Taif, Saudi Arabia.

Background Presbyopia is a physiological condition arising due to the loss of accommodation within the crystalline lens. One of the most widely accepted theories of the mechanism of accommodation was that in response to ciliary muscle contraction, the crystalline lens thickness increases, the lens diameter decreases, and both the anterior and posterior curvature of the lens increase, resulting in an increase in lenticular power therefore, accommodation. A contrasting theory suggests that ciliary muscle contraction leads to a selective increase in equatorial zonular tension, with the lens equator moving toward the sclera and the equatorial diameter of the lens increasing. This results in a change of lens optical power. Until now, clinical approaches to correct presbyopia have included monovision, multifocality, and extended depth of focus, all three of which can be achieved surgically on the cornea or by lens surgery. Methods This was a cross-sectional study adopted among patients who had Presbyond surgery in Taif City, Saudi Arabia, and were aged 40 years and older. The data was collected by conducting phone interviews to increase the response rate with a prepared questionnaire that was studied to achieve equality between participants to determine whether they were satisfied or not about the results after this surgery. The contact information was retrieved based on hospital records about patients who underwent Presbyond surgery. Data was analyzed using IBM SPSS Statistics for Windows, Version 22 (Released 2013; IBM Corp., Armonk, New York, United States). The data was collected for the period beginning on the first of January 2019 until the first of February 2023. Results From the study findings, a significant number of participants (28.1%, n=25) reported experiencing complete improvement and returning to normal life within 1-30 days after surgery. A slightly larger percentage (39.2%, n=35) experienced this within 1-3 months. Most of the participants (80.9%, n=72) reported an overall improvement in their quality of life after the surgery. This included activities such as reading and using a mobile phone. This indicates that the surgery had a positive impact on their daily lives and activities. In terms of recommendations, a total of 49 (55.1%, n=49) participants stated that they were very likely to recommend refractive surgery to a family member or friend experiencing vision problems. The study found that the mean patients' satisfaction score after one month of surgery is 2.494 units higher than the mean satisfaction score before surgery. This difference was statistically significant (p < .001). Conclusion The majority of participants did not experience any problems during the surgery, and most were able to resume their normal activities within a relatively brief period of time. The surgery achieved its goals for the majority of participants, resulting in an improvement in their quality of life. However, some short-term discomfort or adjustment period was reported. Overall, the participants were satisfied with the surgery, with the majority being very likely to recommend it to others. There is room for improvement in addressing concerns such as blurred vision, the need for glasses, and dry eyes. The study also found that patient satisfaction increased significantly after one month of surgery, and the timing of complete improvement and perception of achieving surgical goals were strongly associated with perceived outcomes.

Risk factors for severe morbidity and definitive stoma after elective surgery for sigmoid diverticulitis: a multicenter national cohort study.

BACKGROUND: In the decision to perform elective surgery, it is of great interest to have data about the outcomes of surgery to individualize patients who could safely undergo sigmoid resection. The aim of this study was to provide information on the outcomes of elective sigmoid resection for sigmoid diverticular disease (SDD) at a national level. METHODS: All consecutive patients who had elective surgery for SDD (2010-2021) were included in this retrospective, multicenter, cohort study. Patients were identified from institutional review board-approved databases in French member centers of the French Surgical Association. The endpoints of the study were the early and the long-term postoperative outcomes and an evaluation of the risk factors for 90-day severe postoperative morbidity and a definitive stoma after an elective sigmoidectomy for SDD. RESULTS: In total, 4617 patients were included. The median [IQR] age was 61 [18.0;100] years, the mean ± SD body mass index (BMI) was 26.8 ± 4 kg/m2, and 2310 (50%) were men. The indications for surgery were complicated diverticulitis in 50% and smoldering diverticulitis in 47.4%. The procedures were performed laparoscopically for 88% and with an anastomosis for 83.8%. The severe complication rate on postoperative day 90 was 11.7%, with a risk of anastomotic leakage of 4.7%. The independent risk factors in multivariate analysis were an American Society of Anesthesiologists (ASA) score ≥ 3, an open approach, and perioperative blood transfusion. Age, perioperative blood transfusion, and Hartmann's procedure were the three independent risk factors for a permanent stoma. CONCLUSIONS: This series provides a real-life picture of elective sigmoidectomy for SDD at a national level. TRIAL REGISTRATION: Comité National Information et Liberté (CNIL) (n°920361).

Investigation and drug design for novel molecules from natural products as inhibitors for controlling multiple myeloma disease using in-silico tools.

Multiple myeloma (MM) is a disease that causes plasma cell growth in the bone marrow and immune globulin buildup in blood and urine. Despite recent advances in MM therapy, many still die due to its high mortality rate. A study using computational simulations analyzed 100 natural ingredients from the SANC database to determine if they inhibited the IgH domain, a known cause of multiple myeloma. Natural component Diospyrin inhibited the IgH enzyme with the best binding energy of -10.3 kcal/mol and three carbon-hydrogen bonds, followed by Parviflorone F complex with a binding energy of -10.1 kcal/mol and two conventional-hydrogen bonds. As a result, the Molecular Dynamic simulation was used to test the stability of the two complexes. During the simulation, the Diospyrin molecule dissociated from the protein at roughly 67.5 ns, whereas the Parviflorone F molecule stayed attached to the protein throughout. The latter was the subject of the investigation. The analysis of the production run data revealed that the Parviflorone F molecule exhibits a variety of conformations within the binding pocket while keeping a relatively constant distance from the protein's center of mass. The analysis of the production run data revealed that the Parviflorone F molecule exhibited a variety of conformations within the binding pocket while keeping a relatively constant distance from the protein's center of mass. The root mean square deviation (RMSD) plots for both the protein and complex showed a stable and steady average value of 4.4 Å for the first 82 nanoseconds of manufacture. As a result, the average value increased to 8.3 Å. Furthermore, the components of the binding free energy, as computed by MM-GBSA, revealed that the mean binding energy of the Parviflorone F molecule was -23.88 kcal/mol. Finally, after analyzing all of the examination data, Parviflorone F was identified as a powerful inhibitor of the IgH domain and hence of the MM disease, which requires further in-vivo conformation.Communicated by Ramaswamy H. Sarma.

Early-Onset Myopia and Retinal Detachment without Typical Microcoria or Severe Proteinuria due to a Novel LAMB2 Variant.

PURPOSE: To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin ß-2 (LAMB2) pathogenic variant. DESIGN: Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene. SUBJECTS: Eleven patients (22 eyes) from 4 families. METHODS: Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation. MAIN OUTCOME MEASURES: Ocular features, renal features, and outcomes of retinal detachment repair. RESULTS: The mean age at presentation was 6.0 (range, 1-26) years. None of the study eyes had microcoria, and none of the patients had nephrotic-range proteinuria. The mean refraction and axial length were -7.9 diopters (range, -4.0 to -12.0 diopters) and 25.3 (range, 22.7-27.7) mm, respectively. Eleven eyes (50%) had cataract at presentation. Fifteen eyes had a clear view to the fundus and all showed tessellated myopic fundus, avascular peripheral retina evident clinically or on fluorescein angiography, and rudimentary fovea. Optic disc pallor was observed in 10 eyes (66.7%). Straightened retinal vessels, abnormal vascular emanation (situs inversus) from the optic disc, supernumerary vascular branching at the optic disc, and vascular tortuosity were observed in 10 (66.7%), 2 (13.4%), 2 (13.4%), and 2 (13.4%) eyes, respectively. Discrete areas of punched-out chorioretinal atrophy were observed in 4 (26.7%) eyes. Spectral-domain OCT showed retinal and choroidal thinning in 13 eyes (86.7%), retinoschisis temporal to the fovea in 2 eyes (13.4%), and rudimentary fovea in 15 eyes (100%). Among the 22 eyes, 14 eyes (63.6%) developed rhegmatogenous retinal detachment (RRD), mostly during childhood, of which 5 patients had bilateral RRD. Eight eyes were operated on and 6 (75%) achieved retinal reattachment at the last follow-up. The mean preoperative visual acuity was 20/300 and the mean postoperative visual acuity at the last follow-up was 20/400. CONCLUSIONS: This study describes a distinct phenotype of LAMB2-related disease with a novel, homozygous LAMB2 variant, and further expands the spectrum of ophthalmic and renal features, and the molecular genetic basis, of LAMB2-related disease. Because the typical microcoria and nephrotic-range proteinuria might be absent, the retinal features can guide the diagnosis. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Regulatory T cells in dominant immunologic tolerance.

Regulatory T cells expressing the transcription factor forkhead box protein 3 mediate peripheral immune tolerance both to self-antigens and to the commensal flora. Their defective function due to inborn errors of immunity or acquired insults is associated with a broad range of autoimmune and immune dysregulatory diseases. Although their function in suppressing autoimmunity and enforcing commensalism is established, a broader role for regulatory T cells in tissue repair and metabolic regulation has emerged, enabled by unique programs of tissue adaptability and specialization. In this review, we focus on the myriad roles played by regulatory T cells in immunologic tolerance and host homeostasis and the potential to harness these cells in novel therapeutic approaches to human diseases.

Saccharomyces cerevisiae supplemented diets mitigate the effects of waterborne cadmium toxicity on gilthead seabream (Sparus aurata L.): growth performance, haemato-biochemical, stress biomarkers, and histopathological investigations.

Yeast, Saccharomyces cerevisiae, has been utilized as a probiotic in aqua-feeds to promote growth and alleviate the stress in aquatic animals. On the other hand, cadmium (Cd) toxicity causes serious retardation of growth and welfare status of aquatic animals. The present study was conducted to evaluate the protective role of dietary yeast in mitigating the waterborne Cd toxicity effects on the growth, haemato-biochemical, stress biomarkers, and histopathological investigations of gilthead seabream (Sparus aurata L.). In a 3 × 3 factorial design, the acclimated fish (20-24 g) were randomly distributed into nine treatments in triplicates where they were fed on 0.0% (control), 0.5%, and 1.0% of yeast along with exposure to 0.0, 1.0, and 2.0 mg Cd/L for 60 days. All growth parameters and mRNA expressions of IGF-1 and GH genes as well as haematological parameters were markedly increased with the increase of dietary yeast levels; meanwhile these variables were significantly retarded with Cd exposure. Contradictory effects on the above-mentioned variables were observed with Cd toxicity. In contrast, blood cortisol, glucose, total cholesterol, and triglyceride, lactate dehydrogenase, alanine transaminase, aspartate transaminase, alkaline phosphatase, in addition to DNA fragments % were noticeably increased with Cd toxicity especially at the treatment of 2.0 mg Cd/L, while decreasing with increasing dietary yeast levels. Compared with the control fish group, Cd concentrations in the gill, liver, and muscle tissues of gilthead seabream were higher in Cd-exposed treatments, especially at the treatment of 2.0 mg Cd/L. Deposition of Cd in fish liver was higher than that in gill tissues but lowest Cd residue was observed in muscle tissues. No significant changes in Cd residues in fish organs were observed in yeast-fed fish with no Cd exposure. The Cd exposure negatively affected histological status of gill, liver, and kidney tissues of S. aurata; while feeding Cd-exposed fish on yeast diets lowered the Cd residues in fish organs and recovered the adverse effects of Cd toxicity. Hence, this study recommends the addition of bakery yeast (1.0%) to fish diets to improve the performance, overall welfare, and histopathological status of gilthead seabream, S. aurata.