Significant Pathology Research Articles

Trans-Sinus Implant using TTPHIL-ALL-TILT ®Technique as an alternative to Sinus lifts: A Technical Description and Case Series

Background: Severe atrophy of the maxillary ridge and extended maxillary sinus pneumatisation limits the treatment options available for rehabilitating patients with teeth missing in the posterior maxilla. Sinus lifts followed by bone grafting have become the norm for rehabilitating such patients. Nonetheless, sinus lift procedures can be cumbersome, time-consuming, and uneconomical, especially if patients are in need of immediate function. Objective: This case series describes a unique combination of placing trans-sinus implants using the TTPHIL-ALL-TILT ® technique for treating patients with the atrophied posterior maxilla. Methods: Three different clinical situations have been described where the trans-sinus placement of implants using the TTPHIL-ALL-TILT ® technique was done for managing atrophied posterior maxilla. The first case was that of a single tooth missing in the posterior maxilla, the second of multiple posterior tooth missing (distal extension, partially edentulous condition) and the third being that of a completely edentulous maxilla. The implants were placed in a flapless tilted manner along with double bi-cortical engagement through the maxillary sinus. Results and Discussion: Following prosthetic rehabilitation, clinical reviews were performed after 6 months. In all cases, implant stability was manually checked and no pathological symptoms or signs were recovered at any follow-up visit. Conclusion: Trans-sinus implants using the TTPHIL-ALL-TILT ® technique prove to be a good choice to rehabilitate these three clinical scenarios. All three patients were extremely satisfied with the treatment outcome. This could very well become a convenient treatment alternative to sinus lift procedures.

Left ventricular diastolic dysfunction and transmitral blood flow parameters in patients after COVID-19

Background. People who previously had COVID-19 infection have an increased risk of developing cardiovascular diseases. Left ventricular diastolic dysfunction is an early marker of the development of cardiac pathology. Its early detection is important for the adequate therapy order and dynamic monitoring of patients. In this regard, it seems relevant to study the effect of a recent COVID-19 infection on the left ventricular diastolic function and transmitral blood flow parameters in apparently healthy individuals without clinical and instrumental signs of cardiovascular pathology. The aim of the study. To assess the changes in the diastolic and systolic function of  the left ventricle, its anatomical parameters and transmitral blood flow parameters in two groups of  apparently healthy individuals: those who had and those who had not COVID-19 infection. Materials and methods. Transthoracic echocardiography was performed according to the standard technique and its results were analyzed in 66 examined patients who were recognized as apparently healthy according to the results of  regular comprehensive clinical and instrumental studies. The first group included 30 individuals who underwent an echocardiographic study before or during the COVID-19 pandemic, but did not have a coronavirus infection; the second group consisted of 36 people who recovered from COVID-19. The indicators of the presence of left ventricular diastolic dysfunction and the transmitral blood flow parameters were assessed. The study was approved at a meeting of the Medical Ethics Committee under the Ministry of Health of the Republic of Karelia and of Petrozavodsk State University (Minutes No. 47 of 01.11.2023). Results. The frequency of the left ventricular diastolic dysfunction did not differ in  the  first and second groups of patients. Statistically significant differences were recorded in the average flow deceleration time for both early and late filling of the left ventricle in people who had and did not have COVID-19 infection. A change in the phase structure of the transmitral blood flow may be an early manifestation of intracardiac hemodynamic disorders in people who have recovered from COVID-19.

Utilizing heat maps as explainable artificial intelligence for detecting abnormalities on wrist and elbow radiographs

IntroductionWrist and elbow radiographs, which plays a key role in diagnosing both fractures and degenerative conditions, present a diagnostic challenge due to intricate structures and subtle pathological signs. Artificial intelligence (AI) through deep learning models, has transformed diagnostic imaging, achieving accuracy rates, with explainable AI (XAI) and Gradient-weighted Class Activation Mapping (Grad-CAM) enhancing transparency of AI-driven diagnosis. MethodThe MURA-dataset, a comprehensive collection of musculoskeletal radiographs, specifically focuses on wrist and elbow images, ensuring a spectrum of normal and abnormal conditions. An ensemble of transfer-learning models, including VGG16, VGG19, ResNet, DenseNet, InceptionV3 and Xception, was applied, with implemented Grad-CAM techniques, providing interpretable heat maps. The Dice Similarity Coefficient (DSC) evaluated the algorithm's efficiency in recognizing regions of interest. ResultsThe average test accuracy of the 20 models were 0.81 (0.72–0.84), and 0.60 (0.49–0.73) for the wrist and elbow radiographs, respectively. The highest performing models were VGG16 with a test accuracy of 0.84, and DenseNet169 with a test accuracy of 0.73. The DSC were calculated for the six highest performing models, and agreements between algorithms were found on radiographs with metal, and only minimal agreement for radiographs with fractures. ConclusionThe study employed twenty transfer-learning models on wrist and elbow radiographs presenting accuracy and partial agreement with Grad-CAM technique evaluation. This study enables comprehension of model performance and avenues for potential enhancement. Implication for practiceThe utilization of artificial intelligence, specifically transfer-learning models, could greatly enhance the accuracy and efficiency of diagnosing conditions from wrist and elbow radiographs. Additionally, the application of explainable AI techniques such as Grad-CAM can provide visual validation and transparency, thereby strengthening trust and adoption in clinical settings.

The Minimal Utility of Analyzing Ureteropelvic Junction Tissue at the Time of Pyeloplasty

Introduction: Ureteropelvic junction obstruction is a common cause of upper tract obstruction that often necessitates surgical intervention because of its severe implications. A high proportion of these surgeries include pathologic analysis of this tissue with unclear clinical value. We examined our institution's practices concerning sending the ureteropelvic junction (UPJ) specimens for pathology analysis, its clinical value, and the associated costs for both pediatric and adult cases. Methods: We performed retrospective chart review using Current Procedural Terminology codes for pyeloplasty over 8 years. Clinical variables were extracted from operative reports, path reports, and postoperative clinic notes. Pathology results were classified dichotomously as “benign” or “malignant” and subsequently assigned to 1 of 4 categories—inflammation, fibrosis, muscular hyperplasia, or no atypical findings. Results: Two hundred sixty-nine pyeloplasty surgeries were included, 68% of which were in children. Pathologic analysis was requested in most of the cases (91%), and this was slightly more common in adults (94%) than in pediatric patients (90%). All available pathology reports found benign findings in the UPJ specimen, mostly commonly categorized as “normal.” No cases of malignancy were noted. At the list price for pathologic analysis, $103,027 was spent over 8 years without the discovery of clinically significant pathology findings. Conclusions: There was a lack of clinically meaningful results from pathologic analysis of UPJ specimens excised during pyeloplasty. A UPJ specimen should not be routinely sent for pathologic analysis rather selectively if there is clinical concern for nonbenign etiology of UPJ obstruction.

Delayed closure of the anterior fontanelle in Iron Age children from Zaghunluq, northwestern China.

Delayed closure of the anterior fontanelle is often associated with various disorders. However, the phenomenon might be a normal variation. In this study, the anterior fontanelle was investigated in children from the Iron Age Zaghunluq cemetery in Xinjiang, northwestern China. Age at death was estimated by tooth development/eruption in the children. The anterior fontanelle was visually assessed for delayed fusion. Three out of nine children aged between 3-6 years old from the cemetery had signs of open anterior fontanelle. However, there were no signs of craniofacial pathology or developmental disruption. Delayed closure of the anterior fontanelle might have been a norm in the Iron Age Zaghunluq population. However, it is impossible to determine the reasons behind the high prevalence of delayed AF closure at Zaghunluq. Additional studies are warranted to determine whether this phenomenon is population specific, or diet specific, or just an individual variation.

Polymorphism of the coding gene LGALS-3 rs2274273 as an endogenous factor of the predictive effectiveness of the plasma concentration of galectin-3 in relation to the risk of development of chf on the background of eh in women

Objective. The purpose of the study is to improve the early diagnosis of the development of left ventricular myocardial hypertrophy (LVH) and the formation of prerequisites for chronic heart failure (CHF) in women with essential hypertension, residents of the Podillya region of Ukraine by determining the plasma concentration of galectin-3 in carriers of different polymorphic variants of the LGALS-3 (rs2274273) gene. Material and methods. 180 women of postmenopausal age, average age of 57.34±0.45, residents of the Podillya region of Ukraine, who lived in this territory in the third generation, were examined. The control group consisted of 67 women, average age of 56.43±0.64 years, without signs of cardiovascular pathology and signs of left ventricular hypertrophy (LVH) for other reasons were detected. The main group included 113 women with essential hypertension, of which 62 had essential hypertension with LVH without heart failure (EH II), 51 had essential hypertension with chronic heart failure stage C according to the ESH/ESC 2023 classification. General clinical examination, enzyme immunoassay method for determining the level of galectin-3 in blood plasma, genotyping of the LGALS3 (rs2274273) gene using polymerase chain reaction, and ultrasound of the heart were performed. The statistical processing of the obtained results was carried out using the package of statistical programs SPSS, STATISTICA v. 10.0. Mathematical methods were used: multiple regression stepwise analysis of proportional risks with 95% CI confidence interval, Fisher's linear discriminant analysis with the creation of a mathematical prognostic model, and cluster analysis. Compliance of the frequency distribution of genotypes in the studied populations to the Hardy-Weinberg equilibrium was checked using the MedCalc Software Ltd. Odds ratio calculator. https://www.medcalc.org/calc/odds_ratio.php and calculated the odds ratio (OR) of developing left ventricular myocardial hypertrophy (LVH) and chronic heart failure (CHF).Results. In patients with EH and CHF, carrying the A allele of the LGALS-3 (rs2274273) gene was associated with a more severe degree of diastolic dysfunction and reduced LVEF compared with carriers of the GG genotype, and higher plasma levels of galectin-3 were also recorded, which were associated with a more significant deterioration structural and functional indicators of the myocardium. With the help of cluster analysis, it was found that carriers of the A allele of the LGALS-3 (rs2274273) gene are more likely to be included in unfavorable cluster 1. In contrast, in cluster 2, with a more favorable course of the disease, carriers of the GG genotype and carriers of the A allele occur with almost the same frequency. Conclusions. In postmenopausal women, residents of the Podillya region of Ukraine, carrying the A allele of the LGALS-3 (rs2274273) gene is associated with a more severe course of EH with the development of LVH, a higher concentration of galectin-3 in the blood plasma, and the formation of CHF with reduced LVEF when compared with carriers of the genotype GG.

An unusual presentation of ossified spinal meningioma: case report and literature review.

Spinal meningioma is a common intraspinal tumor, which mainly occurs in the thoracic spine. Ossified meningioma (OSM) is an extremely rare histological variant. Our article reports a rare patient with dorsal complete OSM and reviews this subject. A 68-year-old woman presented with a one-year history of progressive weakness in both lower limbs with gait disturbance. Physical examination revealed hypoesthesia with a sensory level below T10. Babinski and pathological signs on both sides were weakly positive. Magnetic resonance imaging (MRI) showed a mass at the T10 to T11 level causing severe compression of the spinal cord. Computed tomography (CT) showed complete ossification of the mass. 18F-Fluoro-deoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan combined with MRI revealed that the mass was an intradural extramedullary high-density ossified nodule. The patient underwent a gross total resection of the mass and pathologic examination indicated that the mass was a meningioma with diffused psammomatous bodies. We identified a rare case of dorsal complete OSM occurring in a 68-year-old woman. After complete surgical resection, although there were complications such as cerebral fluid leakage and fever, the patient finally recovered with a satisfactory result.

PP2C phosphatases Ptc1 and Ptc2 dephosphorylate PGK1 to regulate autophagy and aflatoxin synthesis in the pathogenic fungus Aspergillus flavus.

Aspergillus flavus is a model filamentous fungus that can produce aflatoxins when it infects agricultural crops. This study evaluated the protein phosphatase 2C (PP2C) family as a potential drug target with important physiological functions and pathological significance in A. flavus. We found that two redundant PP2C phosphatases, Ptc1 and Ptc2, regulate conidia development, aflatoxin synthesis, autophagic vesicle formation, and seed infection. The target protein phosphoglycerate kinase 1 (PGK1) that interacts with Ptc1 and Ptc2 is essential to regulate metabolism and the autophagy process. Furthermore, Ptc1 and Ptc2 regulate the phosphorylation level of PGK1 S203, which is important for influencing aflatoxin synthesis. Our results provide a potential target for interdicting the toxicity of A. flavus.

Pathological, biochemical and hormonal changes associated with prolonged administration of methanol extract of <i>Garcinia kola</i> seed in adult male Wistar rats.

Garcinia kola (GK) seed is believed to possess aphrodisiac properties hence its traditional use to manage erectile dysfunctions in man. However, there has been conflicting reports of its long-term effects on the male reproductive organs. In this study, the effect of varying doses of methanol extract of GK on testicular function and structure in Wistar rats was evaluated. Forty adult male rats (350-360g) were randomly divided into 4 groups. Groups 1, 2 and 3 received oral doses of 600mg/kg, 400mg/kg and 100mg/kg of the extract daily, respectively for 70 days while group 4 (control group) received normal saline (0.9% NaCl). Blood samples were collected fortnightly from each rat for serum chemistry and testosterone analysis. At termination, the testes, epididymides and livers were harvested, weighed and fixed in 10% neutral buffered formalin and processed for histopathology. The results were presented as mean ± standard error of mean (SEM) and analyzed using one way analysis of variance (ANOVA) at P< 0.05. Dose-related pathological changes were observed in the testes and epididymides. Testicular weight decreased significantly (p<0.05) in 400mg/kg and 600mg/kg groups compared to the control group. There was testicular necrosis associated with distortion of the seminiferous tubular wall and reduced seminiferous tubular diameter. Seminiferous tubules had reduced germinal epithelial thickness along with an absence of viable spermatids and spermatozoa. Serum testosterone levels decreased progressively (p < 0.01) in groups 1 and 2 while those of groups 3 and 4 remain unchanged. The results established that ingestion of methanol extracts of GK seed at the dose of 400mg/kg and 600mg/kg produced significant gonadal pathology in adult male Wistar rats despite the absence of remarkable hepatic biochemical and structural changes.

Microstructural Changes in the Spinothalamic Tract of CPSS Patients: Preliminary Results from a Single-Center Diffusion-Weighted Magnetic Resonance Imaging Study.

Chronic pain after spinal surgery (CPSS), formerly known as failed back surgery syndrome, encompasses a variety of highly incapacitating chronic pain syndromes emerging after spinal surgery. The intractability of CPSS makes objective parameters that could aid classification and treatment essential. In this study, we investigated the use of cerebral diffusion-weighted magnetic resonance imaging. Cerebral 3T diffusion-weighted (DW-) MRI data from adult CPSS patients were assessed and compared with those of healthy controls matched by age and gender. Only imaging data without relevant artefacts or significant pathologies were included. Apparent diffusion coefficient (ADC) maps were calculated from the b0 and b1000 values using nonlinear regression. After skull stripping and affine registration of all imaging data, ADC values for fifteen anatomical regions were calculated and analyzed with independent samples T-tests. A total of 32 subjects were included (sixteen CPSS patients and sixteen controls). The mean ADC value of the spinothalamic tract was found to be significantly higher in CPSS patients compared with in healthy controls (p = 0.013). The other anatomical regions did not show statistically different ADC values between the two groups. Our results suggest that patients suffering from CPSS are subject to microstructural changes, predominantly within the cerebral spinothalamic tract. Additional research could possibly lead to imaging biomarkers derived from ADC values in CPSS patients.

COVID-19-induced cardiovascular complexities

This study aimed to investigate the features of the clinical course of COVID-19 in combination with the pathology of the cardiovascular system (CVS). A prospective study was carried out. The main group (n=150) consisted of patients with changes in the cardiovascular system associated with COVID-19, i.e. newly diagnosed CV pathology, and patients with exacerbation of cardiac pathology against the background of COVID-19. The comparison group (n=154) included patients with COVID-19, but without any significant concomitant cardiac pathology. The average age of patients in the main group was 67.7 years (from 47 to 86 years), in the comparison group of 66.1 years (from 48 to 88 years). The study groups were representative and did not differ statistically in the nature of COVID-19 symptoms and the degree of lung involvement. Among the cardiac pathology, progressing or first occurring against the background of infection with COVID-19, in most cases, arterial hypertension of II-III degree (60.0%), coronary heart disease (48.7%), arrhythmias (23.3%) were diagnosed. Echocardiographic abnormalities included right ventricular dysfunction (22.7%), left ventricular contractility disorders (18.7%), with decreased ejection fraction (17.3%), diastolic dysfunction (14.0%), and toxic myocarditis (7.3%). The most significant risk factors were the presence of a burdened medical history (RR=10.39), elevated body mass index over 30 (RR=2.63) and diabetes mellitus (RR=1.55). In patients with COVID-19 in combination with CVS pathology, a relatively high incidence of acute onset (64.0% vs. 44.2%; p<0.001), respiratory failure (83.7% vs. 62.0%; p<0.001), admission to the intensive care unit (25.3% vs. 11.7%; p=0.004), development of acute respiratory distress syndrome (20.0% vs. 9.1%; p=0.012), hospital mortality (10.7% vs. 2.7%; p=0.006). Cardiac manifestations of COVID-19 included focal or global myocardial inflammation, ventricular dysfunction, heart failure, and arrhythmias. A high frequency of acute onset of the disease, respiratory failure and hospital mortality is determined.

COVID-19-induced cardiovascular complexities

This study aimed to investigate the features of the clinical course of COVID-19 in combination with the pathology of the cardiovascular system (CVS). A prospective study was carried out. The main group (n=150) consisted of patients with changes in the cardiovascular system associated with COVID-19, i.e. newly diagnosed CV pathology, and patients with exacerbation of cardiac pathology against the background of COVID-19. The comparison group (n=154) included patients with COVID-19, but without any significant concomitant cardiac pathology. The average age of patients in the main group was 67.7 years (from 47 to 86 years), in the comparison group of 66.1 years (from 48 to 88 years). The study groups were representative and did not differ statistically in the nature of COVID-19 symptoms and the degree of lung involvement. Among the cardiac pathology, progressing or first occurring against the background of infection with COVID-19, in most cases, arterial hypertension of II-III degree (60.0%), coronary heart disease (48.7%), arrhythmias (23.3%) were diagnosed. Echocardiographic abnormalities included right ventricular dysfunction (22.7%), left ventricular contractility disorders (18.7%), with decreased ejection fraction (17.3%), diastolic dysfunction (14.0%), and toxic myocarditis (7.3%). The most significant risk factors were the presence of a burdened medical history (RR=10.39), elevated body mass index over 30 (RR=2.63) and diabetes mellitus (RR=1.55). In patients with COVID-19 in combination with CVS pathology, a relatively high incidence of acute onset (64.0% vs. 44.2%; p<0.001), respiratory failure (83.7% vs. 62.0%; p<0.001), admission to the intensive care unit (25.3% vs. 11.7%; p=0.004), development of acute respiratory distress syndrome (20.0% vs. 9.1%; p=0.012), hospital mortality (10.7% vs. 2.7%; p=0.006). Cardiac manifestations of COVID-19 included focal or global myocardial inflammation, ventricular dysfunction, heart failure, and arrhythmias. A high frequency of acute onset of the disease, respiratory failure and hospital mortality is determined.

CYTOMORPHOLOGICAL STRUCTURE OF THE GREATER OMENTUM IN BORDERLINE OVARIAN TUMOR

The article describes the cytomorphological organization of the greater omentum in borderline ovarian tumor. The cytomorphology of the greater omentum in this pathology has not been studied enough, so this work is of scientific interest, and the topic under study is relevant. The aim of the research was to study the structural organization of the greater omentum in borderline ovarian tumor. Materials and methods. Information on the cytomorphological structure of the main parts of the greater omentum was studied, described and analyzed. These include adipose, lymphoid and epithelial tissue. The cytomorphological structure features of the greater omentum were studied in 20 patients who were treated for borderline ovarian tumor. Study results. The studied preparations of greater omentaries demonstrate a normal structure of this organ without manifestations of pathological signs or other specific changes. The adipoid and loose connective tissue in the greater omentum is well expressed, and the vascular system of the organ is also developed. Lymphoid structures are found in large numbers. They are responsible for implementing immune protection and thus can restrain dissemination of atypical cells and prevent their spread. Conclusions. In borderline ovarian tumor, the greater omentum is an organ that prevents the progression of the disease and reduces the likelihood of its recurrence. It is necessary to accurately determine the histological type of tumor intraoperatively in order to avoid omentectomy in case of suspected malignancy of the tumor.

A narrative review on malleable and inflatable penile implants: choosing the right implant for the right patient.

A penile prosthesis/implant is an excellent option for men with erectile dysfunction refractory to medical treatment or with contraindications to medical management. In this narrative review, we discuss the different types of penile prostheses and the considerations for patient and device selection to maximize satisfaction. There are three main prosthesis types to choose from: three-piece inflatable devices, two-piece inflatable devices, and malleable/semirigid devices. The three-piece devices are the gold standard in advanced economy countries but require reservoir placement and manual dexterity, which can be limiting to some patients. The two-piece inflatable devices are a good option for patients who have standard-sized penises, lack significant penile pathology, have limited dexterity issues, or should avoid reservoir placement due to potential complications. The malleable devices are popular in countries where insurance coverage is limited but are increasingly used in advanced economy countries for length conservation in specific patient populations. Finally, not every patient needs an implant, and assessing partner sexual function is an important consideration for patient-partner satisfaction. Surgeons need to be familiar with the strengths and limitations of each device and the patient characteristics that will yield the best outcome from penile prosthesis surgery.

Chronic mandibular osteomyelitis associated with a novel probable Kocuria sp in a sugar glider (Petaurus breviceps)

Dental disease in sugar gliders (Petaurus breviceps) is understudied, with only limited clinical and pathological data available. An approximately 7-year-old female sugar glider presented to its primary care veterinarian for a decline in food intake, rapid weight loss and a mass involving the rostral mandible. At necropsy, the mandibular mass effaced most of the rostral mandible and adjacent musculature. Histologically, the mandible was disrupted by nodular infiltrates of variably degenerate neutrophils and macrophages encased in granulomatous inflammation and fibrous connective tissue. Within the neutrophilic cell population were segments of fragmented, necrotic bone and cloud-like colonies of gram-positive cocci. Aerobic culture yielded a heavy, pure growth of a gram-positive coccus morphologically consistent with those identified in the lesions, which was identified as a presumptively novel Kocuria sp by polymerase chain reaction and sequencing of the 16S rRNA gene. This is the first description of Kocuria infection in association with clinically significant pathology in an animal. Although isolated as a pure growth, Kocuria sp cannot be confirmed as the sole cause of lesion formation due to the case chronicity and potential for unculturable, polymicrobial infections. This report adds to our understanding of the clinical and pathological aspects of dental disease in sugar gliders.

Anatomical variations and abnormalities of the maxillary region and clinical implications: A systematic review and metaanalysis.

The objective of this review is to investigate and analyze the anatomical variations present in the maxillary sinus (MS), through the examination of the prevalence of these variations, as well as the corresponding prevalence of clinically significant pathologies and complications associated with them. The search process was carried out in the following databases; MEDLINE, SCIELO, WOS, CINHAL, SCOPUS, and GOOGLE SCHOLAR, using as search terms; "Maxillary bone," "Maxillary sinus," "Paranasal sinus," "Anatomical variations," "Sinusitis" and "Clinical anatomy." A total of 26 articles and 12969 samples were included, from which 12,594 subjects had their sex recorded giving a total of 5802 males and 6792 females. The variants reported by the included were Haller cells, Concha Bullosa, Number of septa, Hypoplastic sinus, Agger Nasi, Thickening of the MS mucosa, Deviation of the nasal septum, Accessory ostium, and Onodi cells. Among the mentioned, the ones that presented the greatest number of studies (between 8 and 10 studies included) were: the Haller Cells, the Concha Bullosa, and the Number of septa, where prevalence was 0.30, 0.36, 0.39 respectively. These variations can lead to sinusitis, cause some types of tumors, or affect neighboring structures that could be compromised by this variation. As a result, it is certainly complex to distinguish the presence of anatomical variations from pathological abnormalities. Therefore, knowledge of the different variations and their clinical relationships could be a useful asset for clinicians dedicated to this region.

Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.

Group A Streptococcus Vaccine Targeting the Erythrogenic Toxins SpeA and SpeB Is Safe and Immunogenic in Rabbits and Does Not Induce Antibodies Associated with Autoimmunity.

Group A streptococcus (GAS) is a global pathogen associated with significant morbidity and mortality for which there is currently no licensed vaccine. Vaccine development has been slow, mostly due to safety concerns regarding streptococcal antigens associated with autoimmunity and related complications. For a GAS vaccine to be safe, it must be ensured that the antigens used in the vaccine do not elicit an antibody response that can cross-react with host tissues. In this study, we evaluated the safety of our GAS vaccine candidate called VaxiStrep in New Zealand White rabbits. VaxiStrep is a recombinant fusion protein comprised of streptococcal pyrogenic exotoxin A (SpeA) and exotoxin B (SpeB), also known as erythrogenic toxins, adsorbed to an aluminum adjuvant. The vaccine elicited a robust immune response against the two toxins in the rabbits without any adverse events or toxicity. No signs of autoimmune pathology were detected in the rabbits' brains, hearts, and kidneys via immunohistochemistry, and serum antibodies did not cross-react with cardiac or neuronal tissue proteins associated with rheumatic heart disease or Sydenham chorea (SC). This study further confirms that VaxiStrep does not elicit autoantibodies and is safe to be tested in a first-in-human trial.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Prevalence of subclinical keratoconus and impact on adults undergoing routine, uncomplicated age-related cataract extraction

AimTo determine the prevalence of subclinical keratoconus (SKCN) among individuals undergoing routine, uncomplicated age-related cataract surgery and its impact on visual and refractive outcomes.Patient and MethodsAt a major academic ophthalmology department in the United States, we reviewed records of patients aged 50 years and older who underwent surgery from January 2011 to June 2022. We excluded patients who had poor-quality or unreliable tomographic data, previous corneal surgery, keratorefractive procedures, and significant vision-limiting ocular pathology. We defined SKCN if an eye had a Belin-Ambrósio enhanced ectasia index (BAD-D) ≥1.7, which was based on the results of a meta-analysis of large studies. In addition to the BAD-D cutoff, the eye had to deviate significantly on at least one of seven additional parameters: 1) posterior elevation at thinnest point, 2) index of vertical asymmetry, 3) index of surface variation, 4) total front higher order aberrations, 5) front vertical coma, 6) front secondary vertical coma, 7) back vertical coma. An individual had SKCN if at least one eye met the tomography-based classification and did not have manifest KCN in either eye. Visual and refractive outcomes data were acquired from patients of one experienced cataract surgeon with cases done from July 2021 to June 2022. Statistical significance was set at p < 0.05.ResultsAmong 5592 eyes from 3828 individuals, the prevalence of SKCN was 24.7% (95% CI, 23.4 – 26.1, 945 individuals), and the prevalence of KCN was 1.9% (95% CI, 1.6 – 2.4, 87 individuals). The prevalence of SKCN did not increase with age and was more prevalent among females and non-white races. Median post-operative month one distance-corrected visual acuity (DCVA) and proportion of eyes with improvement in DCVA were similar between normal and SKCN eyes. The proportion of eyes reaching ±0.5 and ±1.0 diopter within the refractive target were similar between normal and SKCN eyes.ConclusionSKCN is highly prevalent and should be detected but is unlikely to have a significant deleterious effect on outcomes in routine, uncomplicated cataract surgery.