Signalling input from divergent pathways subverts B cell transformation.

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.

Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3-/- naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3-/- B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3-/- B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.

SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis.

Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke1, is initiated by passage of low-density lipoprotein (LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating LDL enters the artery wall to instigate atherosclerosis. Here we show in mice that scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-amino-acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes internalization of SR-B1 and transport of LDL by coupling the binding of LDL to SR-B1 with activation of RAC1. The expression of SR-B1 and DOCK4 is increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. These findings challenge the long-held concept that atherogenesis involves passive movement of LDL across a compromised endothelial barrier. Interventions that inhibit the endothelial delivery of LDL into artery walls may represent a new therapeutic category in the battle against cardiovascular disease.

Utilizing genomic signatures to gain insights into the dynamics of SARS-CoV-2 through Machine and Deep Learning techniques.

The global spread of the SARS-CoV-2 pandemic, originating in Wuhan, China, has had profound consequences on both health and the economy. Traditional alignment-based phylogenetic tree methods for tracking epidemic dynamics demand substantial computational power due to the growing number of sequenced strains. Consequently, there is a pressing need for an alignment-free approach to characterize these strains and monitor the dynamics of various variants. In this work, we introduce a swift and straightforward tool named GenoSig, implemented in C++. The tool exploits the Di and Tri nucleotide frequency signatures to delineate the taxonomic lineages of SARS-CoV-2 by employing diverse machine learning (ML) and deep learning (DL) models. Our approach achieved a tenfold cross-validation accuracy of 87.88% (± 0.013) for DL and 86.37% (± 0.0009) for Random Forest (RF) model, surpassing the performance of other ML models. Validation using an additional unexposed dataset yielded comparable results. Despite variations in architectures between DL and RF, it was observed that later clades, specifically GRA, GRY, and GK, exhibited superior performance compared to earlier clades G and GH. As for the continental origin of the virus, both DL and RF models exhibited lower performance than in predicting clades. However, both models demonstrated relatively higher accuracy for Europe, North America, and South America compared to other continents, with DL outperforming RF. Both models consistently demonstrated a preference for cytosine and guanine over adenine and thymine in both clade and continental analyses, in both Di and Tri nucleotide frequencies signatures. Our findings suggest that GenoSig provides a straightforward approach to address taxonomic, epidemiological, and biological inquiries, utilizing a reductive method applicable not only to SARS-CoV-2 but also to similar research questions in an alignment-free context.

Treatment modalities and survival outcomes in prostate cancer parenchymal brain metastasis.

BACKGROUND: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes. METHODS: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups. RESULTS: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022). CONCLUSIONS: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

Distinct and dynamic activation profiles of circulating dendritic cells and monocytes in mild COVID-19 and after yellow fever vaccination.

Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID-19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS-CoV-2 infected outpatients with mild disease and compared it to the response of healthy individuals to yellow fever vaccine virus YF17D as a model of a well-coordinated response to viral infection. In SARS-CoV-2-infected outpatients circulating DCs were persistently reduced for several weeks whereas after YF17D vaccination DC numbers were decreased temporarily and rapidly replenished by increased proliferation until 14 days after vaccination. The majority of COVID-19 outpatients showed high expression of CD86 and PD-L1 in monocytes and DCs early on, resembling the dynamic after YF17D vaccination. In a subgroup of patients, low CD86 and high PD-L1 expression were detected in monocytes and DCs coinciding with symptoms, higher age, and lower lymphocyte counts. This phenotype was similar to that observed in severely ill COVID-19 patients, but less pronounced. Thus, prolonged reduction and dysregulated activation of blood DCs and monocytes were seen in a subgroup of symptomatic non-hospitalized COVID-19 patients while a transient coordinated activation was characteristic for the majority of patients with mild COVID-19 and the response to YF17D vaccination.

Comparative validation of automated presurgical tractography based on constrained spherical deconvolution and diffusion tensor imaging with direct electrical stimulation.

OBJECTIVES: Accurate presurgical brain mapping enables preoperative risk assessment and intraoperative guidance. This cross-sectional study investigated whether constrained spherical deconvolution (CSD) methods were more accurate than diffusion tensor imaging (DTI)-based methods for presurgical white matter mapping using intraoperative direct electrical stimulation (DES) as the ground truth. METHODS: Five different tractography methods were compared (three DTI-based and two CSD-based) in 22 preoperative neurosurgical patients undergoing surgery with DES mapping. The corticospinal tract (CST, N = 20) and arcuate fasciculus (AF, N = 7) bundles were reconstructed, then minimum distances between tractograms and DES coordinates were compared between tractography methods. Receiver-operating characteristic (ROC) curves were used for both bundles. For the CST, binary agreement, linear modeling, and posthoc testing were used to compare tractography methods while correcting for relative lesion and bundle volumes. RESULTS: Distance measures between 154 positive (functional response, pDES) and negative (no response, nDES) coordinates, and 134 tractograms resulted in 860 data points. Higher agreement was found between pDES coordinates and CSD-based compared to DTI-based tractograms. ROC curves showed overall higher sensitivity at shorter distance cutoffs for CSD (8.5 mm) compared to DTI (14.5 mm). CSD-based CST tractograms showed significantly higher agreement with pDES, which was confirmed by linear modeling and posthoc tests (PFWE < .05). CONCLUSIONS: CSD-based CST tractograms were more accurate than DTI-based ones when validated using DES-based assessment of motor and sensory function. This demonstrates the potential benefits of structural mapping using CSD in clinical practice.

Synergistic immunomodulatory effect of synbiotics pre- and postoperative resection of pancreatic ductal adenocarcinoma: a randomized controlled study.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly immunosuppressive microenvironment. This single-blind, randomized study aimed to evaluate the synergistic immunomodulatory effects of synbiotics (probiotics and inulin prebiotics), as well as their impact on postoperative complications and outcomes, compared to the use of probiotics alone. Ninety patients diagnosed with PDAC were enrolled and randomly assigned into three groups: the placebo group, the probiotics group (receiving a mixture of ten strains of Lactobacillus, Bifidobacterium, and Streptococcus bacteria at a dose of 25 billion CFUs), and the synbiotics group (the same probiotics along with inulin prebiotics). The interventions were administered for 14 days before the surgery and continued for one month postoperatively. Tumor tissue infiltration of CD8 + T cells and the expression of IFN γ were assessed by immunohistochemistry (IHC). Inflammatory cytokines concentrations, including Il 1 B, IL 6, and IL 10, were evaluated as well by ELISA at various time points pre- and postoperative. Furthermore, patients were followed up after the surgery to assess postoperative short-term outcomes. Our results showed a significant elevation of CD8 + T cell proportion and IFN γ expression in the synbiotics group compared to the probiotics group (p = 0.049, p = 0.013, respectively). Inflammatory cytokines showed a significant gradual decrease in the synbiotics group compared to placebo and probiotics-treated groups (p = 0.000 for both). Administration of synbiotics and probiotics significantly decreased the rate of postoperative complications including anastomotic leakage, diarrhea, and abdominal distension (p = 0.032, p = 0.044, p = 0.042, respectively), with a remarkable reduction in bacteremia in the synbiotics group. These results revealed that this synbiotics formulation potentially enhances the immune response and reduces complications associated with surgery.Clinical trial identification: NCT06199752 (27-12-2023).

Development of transgenic Paulownia trees expressing antimicrobial thionin genes for enhanced resistance to fungal infections using chitosan nanoparticles.

There is an increasing focus on genetically altering Paulownia trees to enhance their resistance against fungal infections, given their rapid growth and quality wood production. The aim of this research was to establish a technique for incorporating two antimicrobial thionin genes, namely thionin-60 (thio-60) and thionin-63 (thio-63), into Paulownia tomentosa and Paulownia hybrid 9501 through the utilization of chitosan nanoparticles. The outcomes revealed the successful gene transfer into Paulownia trees utilizing chitosan nanoparticles. The effectiveness of thionin proteins against plant pathogens Fusarium and Aspergillus was examined, with a specific focus on Fusarium equiseti due to limited available data. In non-transgenic Paulownia species, the leaf weight inhibition percentage varied from 25 to 36 %, whereas in transgenic species, it ranged from 22 to 7 %. In general, Paulownia species expressing thio-60 displayed increased resistance to F. equiseti, while those expressing thio-63 exhibited heightened resistance to A. niger infection. The thionin proteins displayed a strong affinity for the phospholipid bilayer of the fungal cell membrane, demonstrating their capability to disrupt its structure. The transgenic plants created through this technique showed increased resistance to fungal infections. Thionin-60 demonstrated superior antifungal properties in comparison to thio-63, being more effective at disturbing the fungal cell membrane. These findings indicate that thio-60 holds potential as a novel antifungal agent and presents a promising approach for enhancing the antimicrobial traits of genetically modified Paulownia trees.

Does fully closed-loop automated insulin delivery improve glycaemic control in patients with type 2 diabetes? A meta-analysis of randomized controlled trials.

AIMS: This meta-analysis investigated the efficacy and safety of fully closed-loop automated insulin delivery (AID) in patients with type 2 diabetes. MATERIALS AND METHODS: We systemically searched PubMed, Scopus, Web of Science, and Cochrane Central from inception until April 26, 2023. We included randomized controlled trials (RCTs) comparing fully closed-loop AID versus conventional insulin therapy. The outcomes were pooled as the mean difference (MD) and risk ratio with 95% confidence interval (CI) in the random effect model. Our primary outcome was the proportion of time in the target glucose range (5.6-10 mmol/L, 3.9-10 mmol/L, or 3.9-8 mmol/L, depending on the study). Key secondary outcomes included the proportion of time spent in hyperglycaemia or hypoglycaemia. RESULTS: We included seven RCTs (three crossover and four parallel design), compromising 390 patients. Our analysis showed that compared to the control group, fully closed-loop AID increased the proportion of time spent within the target glucose range by additional 337 min per 24 h (MD = 23.39%, 95% CI [16.64%, 30.14%], p < 0.01), additional 108 min overnight (MD = 22.40%, 95% CI [12.88%, 31.91%], p < 0.01), and additional 258 min during the daytime period (MD = 26.85%, 95% CI [21.06%, 32.63%], p < 0.01). Compared to the control group, the overall time in hyperglycaemia was shortened by 326 min per 24 h (MD = -22.67%, 95% CI [-30.87%, -14.46%], p < 0.01). There was no significant difference between the two groups in terms of overall, overnight, and daytime periods spent in hypoglycaemia. CONCLUSIONS: Our meta-analysis suggests that fully closed-loop AID may improve glycaemic control in patients with type 2 diabetes, particularly for those with more challenging diabetes management. Further research is required to establish the feasibility of implementing these systems in clinical practice. [Correction added on 26 August 2023 after first online publication: Under Results, the first sentence "We included seven RCTs (three crossover and one parallel designs)" has been changed to "We included seven RCTs (three crossover and four parallel designs)".].

Clinical characteristics, functional outcome and socioeconomic impact of ischemic stroke among young Egyptian adults.

BACKGROUND: Stroke in young patients results in disproportionately high societal cost given the productive life-years lost. Little is known about stroke in young Egyptian patients. We aimed to analyze clinicodemographic characteristics, functional outcome and socioeconomic impact of ischemic stroke among young Egyptian adults. METHODS: Prospective, observational cohort study of consecutively recruited patients with acute ischemic stroke (AIS), 18- 50 years, between September 2022-Septemeber 2023 at a tertiary stroke center in the south of Egypt. We recorded baseline demographic and cardiovascular risk factors, stroke severity, stroke subtype according to the TOAST classification, intravenous thrombolysis, employment and ambulation status pre and post stroke, post stroke complications and 90-day functional outcome measured by the modified Rankin Scale (mRS). RESULTS: Our cohort comprised 210 patients, 38.0 (±7.8) years; 89 (42%) females. Mean NIHSS score was 11.2(±4.8); in-hospital case fatality was 9% (19 patients). Dyslipidemia (n=105, 50%), smoking (n=105, 50%), and hypertension (n=67, 32%) were the most prevalent cardiovascular risk factors. At 90 days 58 (29%) patients had a 90-mRS 0-1 and 53 (26%) met criteria for depression diagnosis. Sixty-nine of the 116 employed individuals (59%) remained out of work after 90 days of stroke, 61 of whom were single earners in their household. . 36/60 (60%) thrombolysis-eligible patients received it; an additional 98 otherwise thrombolysis-eligible patients presented >4.5 hours from symptom onset. Patients receiving IV thrombolysis were significantly more likely to have resumed full time work at 90 days (32% vs 11%, p=0.006) but with no significant difference in 90-day mRS. CONCLUSIONS: Young adult AIS patients in Egypt experience high rates of post-stroke depression and face challenges in their ability to work and provide for their families. Since most patients have treatable cardiovascular risk factors and only about two-thirds of eligible patients receive thrombolysis, reinforcing primary prevention, education about early stroke signs and benefits of acute can improve outcomes and have significant potential societal benefit.

Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents.

BACKGROUND: Given the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents. METHODS: This was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA. RESULTS: The ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46-3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49-2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6-9.7]; P < 0.001. CONCLUSIONS: The ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents. IMPACT: Recent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19. To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents. The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19. The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.

Randomized Controlled Trial to Compare Stapled Hemorrhoidopexy Plus Ligation Anopexy With Stapled Hemorrhoidopexy for Managing Grade III and IV Hemorrhoidal Disease.

BACKGROUND: Despite the benefits of the stapled hemorrhoidopexy in the short term, management of prolapsing hemorrhoids, the long-term results are still insufficient regarding recurrent prolapse and patient satisfaction. The current study investigates the addition of ligation anopexy to stapled hemorrhoidopexy. OBJECTIVE: Valuation of adding ligation anopexy to stapled hemorrhoidopexy in improving short-term and long-term results in the treatment of grade III and IV hemorrhoids. DATA SOURCES: Between January 2018 and January 2020, we recruited 124 patients with grade III and IV hemorrhoids at Alexandria Main University Hospital. STUDY SELECTION: Randomized controlled trial. INTERVENTIONS: One hundred twenty-four patients were blindly randomly assigned to 2 equal groups: stapled hemorrhoidopexy (group I) and stapled hemorrhoidopexy plus ligation anopexy (group II). MAIN OUTCOME MEASURES: Recurrence of hemorrhoids and patient satisfaction after a follow-up period of at least 2 years. RESULTS: The average operating time was noticeably less in the stapled hemorrhoidopexy group. Postoperative pain, analgesia requirement, hemorrhoid symptoms score, return to work, complications rate, and quality of life 1 month after surgery were similar between groups. Following a mean follow-up of 36 months (interval, 24-47), in group I, 10 patients (16%) reported recurrent external swelling and/or prolapse compared to 3 patients (5%) in group II ( p = 0.0368). Five patients in group I required redo surgery, whereas no patients required redo surgery in group II. Long-term patient satisfaction was significantly better in group II. LIMITATIONS: It was a single-center experience, so longer follow-up was needed. CONCLUSIONS: Stapled hemorrhoidopexy and stapled hemorrhoidopexy plus ligation anopexy were similar in short-term results with regard to complications rate, hemorrhoids symptoms score, return to work, and quality of life. Long-term results were significantly better with regard to recurrence of external swelling and/or prolapse and patient satisfaction after stapled hemorrhoidopexy plus ligation anopexy. See Video Abstract . TRIAL REGISTRATION NUMBER: Pan African Clinical Trials Registry identifier PACTR20180100293130. ECA PARA COMPARAR LA HEMORROIDOPEXIA CON GRAPAS MS ANOPEXIA POR LIGADURA CON LA HEMORROIDOPEXIA CON GRAPAS PARA EL TRATAMIENTO DE LA ENFERMEDAD HEMORROIDAL DE GRADO III Y IV: ANTECEDENTES:A pesar de los beneficios de la hemorroidopexia con grapas a corto plazo, el manejo de las hemorroides prolapsadas, los resultados a largo plazo aún son insuficientes en cuanto al prolapso recurrente y la satisfacción del paciente, por lo que en nuestro estudio actual agregamos anopexia por ligadura a la hemorroidopexia con grapas.OBJETIVO:Valoración de añadir anopexia por ligadura a la hemorroidopexia con grapas para mejorar los resultados a corto y largo plazo en el tratamiento de las hemorroides grado III-IV.FUENTES DE DATOS:Entre enero de 2018 y enero de 2020 reclutamos a 124 pacientes con hemorroides de grado III-IV en el hospital universitario principal de Alexandria.SELECCIÓN DEL ESTUDIO:Ensayo controlado aleatorio PACTR201801002931307.INTERVENCIÓN(S):124 pacientes fueron asignados al azar de forma ciega a dos grupos iguales, hemorroidopexia con grapas (grupo I) y hemorroidopexia con grapas más anopexia por ligadura (grupo II).PRINCIPALES MEDIDAS DE RESULTADO:Recurrencia de hemorroides y satisfacción del paciente después de un período de seguimiento de al menos dos años.RESULTADOS:El tiempo operatorio promedio fue notablemente menor en el grupo de hemorroidopexia con grapas. Mientras tanto, el dolor posoperatorio, la necesidad de analgesia, la puntuación de los síntomas de hemorroides, el regreso al trabajo, la tasa de complicaciones y la calidad de vida un mes después de la cirugía fueron similares. Después de un seguimiento medio de 36 meses (intervalo: 24-47), el Grupo I, 10 pacientes (16%) se quejaron de inflamación externa recurrente y/o prolapso en comparación con 3 pacientes (5%) en el Grupo II ( p = 0,0368) que requiere rehacer la cirugía. No fue necesaria una nueva cirugía en el grupo II; además, la satisfacción del paciente a largo plazo fue significativamente mejor en el grupo II.LIMITACIONES:Se necesita un seguimiento más prolongado y experiencia en un solo centro.CONCLUSIONES:La hemorroidopexia con grapas comparada con la hemorroidopexia con grapas más anopexia por ligadura fue similar en resultados a corto plazo en cuanto a tasa de complicaciones, puntuación de síntomas de hemorroides, regreso al trabajo y calidad de vida. Los resultados a largo plazo fueron significativamente mejores en cuanto a la recurrencia de la inflamación externa y/o el prolapso y la satisfacción del paciente después de la hemorroidopexia con grapas más anopexia por ligadura. (Traducción-Dr. Mauricio Santamaria ).

Persistent immune abnormalities discriminate post-COVID syndrome from convalescence.

BACKGROUND: Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. METHODS AND RESULTS: Here, we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection or healthy controls. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL-1RA, PDGF-AA). CONCLUSION: These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.

Molecular diagnosis of hen eggs microbiota.

The study was conducted in the Kingdom of Saudi Arabia from 2020 and 2022. The identification, characterization, and evaluation of microbes found in hen eggs was done and it was found very important to prevent contamination caused by various harmful pathogenic microbes. It was found that contaminated eggs harbor various harmful microbes which affect health due to multiple infectious diseases. Hen eggs contain a wide variety of microbes, and several distinct approaches were utilized as well as available for achieving detailed pathogenic information. The information obtained is highly essential for people who consume eggs as a food product.  It is of the utmost importance to protect people from getting sick due to the consumption of contaminated eggs or eggs from chickens that have been infected by various harmful pathogens.  During the experiment, we found that eggs were contaminated directly or the chicken that laid the egg was contaminated. Using molecular genetic analysis, it is possible to detect pathogenic and non-pathogenic contaminations in eggs.  During present studies, the cutting-edge molecular techniques of 16S rRNA gene sequencing technology were used to carry out the objective of performing a molecular identification of the microbial communities infecting eggs. The present research is aimed at determining whether the microbial communities in hen eggs are harmful to humans. The results further indicated most bacteria have the potential to cause illness in humans including Escherichia fergusonii, Salmonella enterica, Pseudocitrobacter faecalis, Yakenella regensburgei, and Erwinia pyrifoliae. Further, research suggested that eggs need to be properly cooked and thoroughly washed to eliminate the possibility of consuming infected eggs.

Molecular diagnosis for camel raw milk microbiota.

The existence of diverse microbes in unprocessed camel milk poses a significant threat to the well-being of a large population, especially infants and toddlers. The objective of this study was to ascertain the existence of microorganisms in unprocessed raw camel milk by employing a molecular-based technique in combination with a histological examination of bacteria. The identification of microbial species was achieved by employing PCR amplification and sequencing of 16s rRNA gene fragments. Various micorganisms found includes the probiotic Lactobacillus species, Staphylococcus succinic, Macrococcus casealyticus, Bacillus cohnii, and Salinicoccus kunmingensis. To prevent microbial contamination in raw milk, it is necessary to adequately heat or pasteurise the milk and to wash and sterilise the udder before milking the camel. This is because raw milk contains microbes that cause multiple diseases. Moreover, in the current era of the COVID-19 pandemics, ensuring proper sanitary conditions in milk and its derivatives might potentially mitigate the transmission of various diseases among consumers shortly. Keywords: camel, microbiota, 16s rRNA gene, PCR.

A Comprehensive Analysis of Reported Adverse Events and Device Failures Associated with Esophageal Self-Expandable Metal Stents: An FDA MAUDE Database Study.

INTRODUCTION: Esophageal Stents are used to maintain esophageal lumen patency in esophageal strictures caused by intrinsic and/or extrinsic malignancies and the occlusion of concomitant esophageal fistulas. While data on the efficacy and safety of esophageal stents exist, comprehensive evaluation of adverse events is limited. The aim of this study is to investigate the reported adverse events and device failures associated with esophageal self-expandable metal stents (SEMS) using the FDA's Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: Post-marketing surveillance data for the esophageal SEMSs were analyzed using the FDA's MAUDE database from January 2014 to December 10, 2023. The outcomes of interest were patient-related adverse events and device failures. Statistical analysis was performed using Microsoft Excel 2010 and SPSS. Pooled numbers and percentages were calculated for each adverse event. Continuous variables underwent analysis using a two-tailed student t test, and significance was set to p ≤ 0.05. RESULTS: During the study period, 548 MAUDE reports revealed 873 device failures and 186 patient-related adverse events. The most common device issues were stent activation, positioning, or separation problems (4 n = 403; 46.2%), followed by device detachment or migration (n = 109, 12.5%), and material problems (n = 93, 10.7%). Patient complications included dysphagia/odynophagia (10%), perforation, pain, and bleeding (each 7.6%). The most common device failures in over-the-wire (OTW) stents and through-the-scope (TTS) stents were activation, positioning, or separation problems (TTS: n = 183, 52.6% vs OTW: n = 220, 41.9%). Compared to OTW stents, TTS stents had higher migration and breakage (13.5% vs. 11.8%, p = 0.24), and (9.2% vs. 6.7%, p = 0.08) respectively, while OTW stents had more challenges with stent advancement or removal (5.1% vs. 0.3%, p < 0.001 and 4.6% vs 3.4%, p = 0.19, respectively) and material problems (14.7% vs. 4.6%, p < 0.001). Activation, positioning, and separation problems were the most frequent device failures in fully covered (FC) and partially covered (PC) stents (FC: n = 62, 32.8%, PC: n = 168, 43.5%). FC stents had higher migration rates (20.6% vs 9.8%, p < 0.001), while PC stents exhibited more material problems (17.4% vs. 5.8%, p < 0.001) and difficulties with advancing the stents (6.7% vs. 0%, p < 0.001). CONCLUSION: Our examination showed a prevalence of reported device complications associated with stent activation, positioning, and separation problems. Dysphagia or odynophagia emerged as the most frequently reported patient complication. Furthermore, our analysis, provides insights into TTS vs. OTW and FC vs. PC esophageal SEMSs, enabling endoscopists and manufacturers to better understand adverse events and potentially optimize device design for future iterations.

Effect of three modalities on emergence agitation among post-traumatic stress disorder patients undergoing laparoscopy: a randomized controlled study.

BACKGROUND AND AIM: Emergence agitation (EA) after general anesthesia is common in patients with post-traumatic stress disorder (PTSD). Due to the recent worldwide events such as the Covid-19 pandemic and wars, PTSD is not rare. Accordingly, a reliable, cost-effective anesthetic protocol to lower the incidence of EA is crucial. Therefore, we aimed to compare three different interventions for avoiding EA in PTSD patients undergoing gynecological laparoscopic surgery. Participants were divided into four groups: 1: performing pre-operative relaxation techniques (deep breathing exercise and progressive muscle relaxation [PMR]); 2: administrating intra-operative Ketamine; 3: applying both previously mentioned strategies and 4 as controls. METHODS: This study was carried out on 144 adult women scheduled for gynecological laparoscopy, randomly allocated into four groups: three intervention groups and a control group (36 each). Women aged 18-45 years old, with a diagnosis of PTSD were included in the study. Patients with a positive history of major neurological, cardiovascular, metabolic, respiratory, or renal disease were excluded. Any patient who reported the use of psychiatric drugs were also excluded from the study. Data was analyzed using IBM SPSS Statistics software version 26. Kolmogorov- Smirnov was used to verify the normality of the distribution of variables. Odds ratio was calculated to clarify the strength and direction of the association between intervention groups and control. Data was deemed significant at a p-value ≤0.05. RESULTS: Heart rate (HR) and Mean Arterial Blood Pressure (MABP) intra-operative and post-operative till 24 hours were significantly lower in groups 1, 2, and 3 compared to group 4 (p<0.001). There was a significant statistical difference in the intraoperative HR percentage decrease. MABP percentage decrease post-operative was higher in all the intervention groups with no statistically significant difference, except for group 1 compared to group 4, which was statistically significant (12.28 ± 11.77 and 6.10 ± 7.24, p=0.025). Visual Analogue Scale measurements were significantly less in the intervention groups 1, 2, and 3 compared to group 4. On Riker sedation-agitation scores, group 1 was 85 times more likely to be non-agitated (85 (15.938 - 453.307), p<0.001), group 2 was 175 times more likely to be non-agitated (175 (19.932-1536.448), p<0.001) and group 3 was protected against agitation. CONCLUSION: Pre-operative relaxation techniques (breathing exercises and PMR) significantly lowered HR, MABP, VAS score, and EA than controls. These effects were not significantly different from intra-operative ketamine injection or the combination of both (relaxation techniques and ketamine). We recommend routine pre-operative screening for PTSD and the application of relaxation techniques (breathing exercises and PMR) in the pre-operative preparation protocol of PTSD-positive cases as well as routine practical application of preoperative relaxation techniques. Further studies on using pre-operative relaxation techniques in general could be cost-effective.

Development and initial validation of the cannabis-related psychosis risk literacy scale (CPRL): a multinational psychometric study.

BACKGROUND: Public education efforts to address and reduce potential harms from cannabis use in Arab countries are either slow or inexistent, and do not follow the steadily increasing trends of cannabis use in Arab youth. Several decades of research on substance use, it can be suggested that being aware of, and knowing about, psychosis risk related to cannabis can at least limit the consumption of the substance. Motivated by a lack of measures specifically designed to measure literacy about cannabis-related psychosis risk in younger populations, and based on an extensive literature review, we aimed to create and validate a new self-report scale to assess the construct, the Cannabis-related Psychosis Risk Literacy Scale (CPRL), in the Arabic language. METHOD: A cross-sectional study was carried-out during the period from September 2022 to June 2023, enrolling 1855 university students (mean age of 23.26 ± 4.96, 75.6% females) from three Arab countries (Egypt, Kuwait and Tunisia). RESULTS: Starting from an initial pool of 20 items, both Exploratory Factor Analysis and Confirmatory Factor Analysis suggested that the remaining 8 items loaded into a single factor. The scale demonstrated good internal consistency, with both McDonald omega and Cronbach's alpha values exceeding 0.7 (omega = 0.85 / alpha = 0.85). The CPRL showed measurement invariance across gender and country at the configural, metric, and scalar levels. Concurrent validity of the CPRL was established by correlations with less favourable attitudes towards cannabis (r = -.14; p <.001). In addition, higher literacy levels were found in students who never used cannabis compared to lifetime users (4.18 ± 1.55 vs. 3.44 ± 1.20, t(1853) = 8.152, p <.001). CONCLUSION: The newly developed CPRL scale offers a valid and reliable instrument for assessing and better understanding literacy about cannabis-related psychosis risk among Arabic-speaking young adults. We believe that this new scale is suitable as a screening tool of literacy, as an instrument for measuring the effect of public education interventions aimed at promoting cannabis-related psychosis risk literacy among young people, and as a research tool to facilitate future studies on the topic with a wider application.

Efficacy of Repeated Low-Level Red Light (RLRL) therapy on myopia outcomes in children: a systematic review and meta-analysis.

BACKGROUND: Myopia is the most prevalent form of refractive error that has a major negative impact on visual function and causes blurring of vision. We aimed to determine if Repeated Low-Level Red Light (RLRL) treatment is beneficial in treating childhood myopia in terms of axial length (AL), spherical equivalent refraction (SER), and sub foveal choroidal thickness (SFCT). METHODS: This systematic review was performed on RLRL for treatment of myopia in children compared to single vision spectacles (SVS). We employed the search strategy with key terms myopia and low-level light therapy then we searched PubMed, Scopus, Cochrane, and Web of Science databases. The mean differences (MD) were used to evaluate the treatment effects. Heterogeneity was quantified using I2 statistics and explored by sensitivity analysis. RESULTS: Five randomized controlled trials (RCTs) were included in our meta-analysis with a total of 833 patients, 407 in treatment group and 426 in control group. At a 3 month follow up period, pooled studies show a statistical difference in AL between RLRL and SVS group (MD = -0.16; 95% CI [-0.19, -0.12], SER (MD = 0.33; 95% CI [0.27, 0.38]), and SFCT (MD = 43.65; 95% CI [23.72, 45.58]). At a 6 month follow up period, pooled studies show a statistical difference in AL between RLRL and SVS group (MD = -0.21; 95% CI [-0.28, -0.15]), SER (MD = 0.46; 95% CI [0.26, 0.65]), and SFCT (MD = 25.07; 95% CI [18.18, 31.95]). At a 12 month follow up period, pooled studies show a statistical difference in AL between RLRL and SVS group (MD = -0.31; 95% CI [-0.42, -0.19]) and SER (MD = 0.63; 95% CI [0.52, 0.73]). CONCLUSION: This is the first systematic review and meta-analysis investigating only RCTs evidence supporting the efficacy of 650 nm RLRL for myopia control in the short term of 3, 6, and 12 months follow up. The present review revealed the clinical significance of RLRL as a new alternative treatment for myopia control with good user acceptability and no documented functional or structural damage. However, the effect of long-term RLRL treatment and the rebound effect after cessation require further investigations.