Quadruple therapies show a higher eradication rate compared to standard triple therapy for Helicobacter pylori infection within the LEGACy consortium. A multicenter observational study in European and Latin American countries.

INTRODUCTION: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations. OBJECTIVE: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America. METHODS: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms. RESULTS: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success. CONCLUSIONS: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents.

Mass vaccination with reassortment-impaired live H9N2 avian influenza vaccine.

Avian influenza poses a severe threat to poultry production and global food security, prompting the development of vaccination programs in numerous countries. Modified live virus (MLV) vaccines, with their potential for mass application, offer a distinct advantage over existing options. However, concerns surrounding reversion, recombination, and unintended transmission have hindered the progress of MLV development for avian influenza in poultry. To address these concerns, we engineered reassortment-impaired, non-transmissible, safe, immunogenic, and protective MLVs through the rearrangement of internal gene segments and additional modifications to the surface gene segments HA and NA. The unique peptide marker aspartic acid-arginine-proline-alanine-valine-isoleucine-alanine-asparragine (DRPAVIAN) was incorporated into HA, while NA was modified to encode the chicken interleukin-18 (ckIL18) gene (MLV-H9N2-IL). In vitro, the MLV-H9N2 and MLV-H9N2-IL candidates demonstrated stability and virus titers comparable to the wild-type H9N2 strain. In chickens, the MLV-H9N2 and MLV-H9N2-IL candidates did not transmit via direct contact. Co-infection studies with wild-type virus confirmed that the altered HA and NA segments exhibited fitness disadvantages and did not reassort. Vaccinated chickens showed no clinical signs upon vaccination, all seroconverted, and the inclusion of ckIL18 in the MLV-H9N2-IL vaccine enhanced neutralizing antibody production. A significant decrease in viral loads post-challenge underscored the protective effect of the MLVs. The MLV-H9N2-IL vaccine, administered via drinking water, proved immunogenic in chickens in a dose-dependent manner, generating protective levels of neutralizing antibodies upon aggressive homologous virus challenge. In summary, this study lays the groundwork for safe MLVs against avian influenza suitable for mass vaccination efforts.

Tattoos: risks and complications, clinical and histopathological approach

Abstract Background Skin modification through tattoos is as old as humanity itself. However, this trend is on the rise, and with the use of different types of pigments and application practices, both cutaneous and systemic complications can arise. Adverse reactions can be grouped into five classes: inflammatory, infectious, neoplastic, aesthetic, and miscellaneous. On histopathology, inflammatory reactions can exhibit a lichenoid pattern or present as spongiotic dermatitis, granulomatous reactions, pseudolymphoma, pseudoepitheliomatous hyperplasia, or scleroderma/morphea-like changes. This article reviews tattoo complications, including their clinical and histopathological characteristics. Methods An open search was conducted on PubMed using the terms "tattoo", "complications", and "skin". No limits were set for period, language, or publication type of the articles. Results Reactions to tattoos are reported in up to 67% of people who get tattooed, with papulonodular and granulomatous reactions being the most common. Some neoplastic complications have been described, but their causality is still debated. Any pigment can cause adverse reactions, although red ink is more frequently associated with them. Patients with pre-existing dermatoses may experience exacerbation or complications of their diseases when getting tattoos; therefore, this procedure is not recommended for this patient group. Conclusions Dermatological consultation is recommended before getting a tattoo, as well as a histopathological examination in case of complications. In patients who develop cutaneous inflammatory reactions following tattooing, additional studies are recommended to investigate systemic diseases such as sarcoidosis, pyoderma gangrenosum, atopic dermatitis, and neoplasms. It is important for physicians to be trained in providing appropriate care in case of complications.

Expansions and contractions of repetitive DNA elements reveal contrasting evolutionary responses to the polyploid genome shock hypothesis in Brachypodium model grasses.

Brachypodium grass species have been selected as model plants for functional genomics of grass crops, and to elucidate the origins of allopolyploidy and perenniality in monocots, due to their small genome sizes and feasibility of cultivation. However, genome sizes differ greatly between diploid or polyploid Brachypodium lineages. We have used genome skimming sequencing data to uncover the composition, abundance, and phylogenetic value of repetitive elements in 44 representatives of the major Brachypodium lineages and cytotypes. We also aimed to test the possible mechanisms and consequences of the "polyploid genome shock hypothesis" (PGSH) under three different evolutionary scenarios of variation in repeats and genome sizes of Brachypodium allopolyploids. Our data indicated that the proportion of the genome covered by the repeatome in the Brachypodium species showed a 3.3-fold difference between the highest content of B. mexicanum-4x (67.97%) and the lowest of B. stacei-2x (20.77%), and that changes in the sizes of their genomes were a consequence of gains or losses in their repeat elements. LTR-Retand and Tekay retrotransposons were the most frequent repeat elements in the Brachypodium genomes, while Ogre retrotransposons were found exclusively in B. mexicanum. The repeatome phylogenetic network showed a high topological congruence with plastome and nuclear rDNA and transcriptome trees, differentiating the ancestral outcore lineages from the recently evolved core-perennial lineages. The 5S rDNA graph topologies had a strong match with the ploidy levels and nature of the subgenomes of the Brachypodium polyploids. The core-perennial B. sylvaticum presents a large repeatome and characteristics of a potential post-polyploid diploidized origin. Our study evidenced that expansions and contractions in the repeatome were responsible for the three contrasting responses to the PGSH. The exacerbated genome expansion of the ancestral allotetraploid B. mexicanum was a consequence of chromosome-wide proliferation of TEs and not of WGD, the additive repeatome pattern of young allotetraploid B. hybridum of stabilized post-WGD genome evolution, and the genomecontraction of recent core-perennials polyploids (B. pinnatum, B. phoenicoides) of repeat losses through recombination of these highly hybridizing lineages. Our analyses have contributed to unraveling the evolution of the repeatome and the genome size variation in model Brachypodium grasses.

Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria.

New 2-pyrrolamidobenzothiazole-based inhibitors of mycobacterial DNA gyrase were discovered. Among these, compounds 49 and 51, show excellent antibacterial activity against Mycobacterium tuberculosis and Mycobacterium abscessus with a notable preference for mycobacteria. Both compounds can penetrate infected macrophages and reduce intracellular M. tuberculosis load. Compound 51 is a potent inhibitor of DNA gyrase (M. tuberculosis DNA gyrase IC50 = 4.1 nM, Escherichia coli DNA gyrase IC50 of <10 nM), selective for bacterial topoisomerases. It displays low MIC90 values (M. tuberculosis: 0.63 µM; M. abscessus: 2.5 µM), showing specificity for mycobacteria, and no apparent toxicity. Compound 49 not only displays potent antimycobacterial activity (MIC90 values of 2.5 µM for M. tuberculosis and 0.63 µM for M. abscessus) and selectivity for mycobacteria but also exhibits favorable solubility (kinetic solubility = 55 µM) and plasma protein binding (with a fraction unbound of 2.9 % for human and 4.7 % for mouse). These findings underscore the potential of fine-tuning molecular properties to develop DNA gyrase B inhibitors that specifically target the mycobacterial chemical space, mitigating the risk of resistance development in non-target pathogens and minimizing harm to the microbiome.

Antifungal Activity of Morinda citrifolia Methanolic Extract against Candida albicans: An In Vitro Study.

Aim: Natural medicine used as an alternative and/or complementary treatment to counteract diseases is of great importance in public health. Therefore, the purpose of the present study was to assess the in vitro antifungal activity of Morinda citrifolia methanolic extract of peel, pulp, and seed against Candida albicans. Materials and Methods: The present study was experimental in vitro and cross-sectional. Eight replicates were prepared in Sabouraud dextrose agar with five wells each, where 0.12% chlorhexidine, distilled water, and methanolic extract of seed, peel, and pulp of Morinda citrifolia fruit were placed at concentrations of 10,690, 8,270, and 6,430 mg/mL, respectively, to evaluate sensitivity according to Duraffourd's scale. In addition, the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined by dilution and agar seeding method. Statistical analysis was performed by analysis of variance (ANOVA) and Tukey's post hoc test, considering a significance level of P < 0.05. Results: The inhibition halos of Morinda citrifolia methanolic extract of seed, peel, and pulp against Candida albicans measured on average 15.94, 11.94, and 11.56 mm, respectively. The MIC of seed, peel, and pulp extract were 1366.25, 2067.5, and 1607.5 mg/mL respectively, whereas the MFC for seed, peel, and pulp extract were 2672.50, 2067.5, and 3215 mg/mL, respectively. Moreover, seed extract presented significantly higher antifungal activity than peel and pulp (P < 0.001). Conclusions: Morinda citrifolia methanolic extract of peel, pulp, and seed showed fungistatic and fungicidal effect against Candida albicans, being this very sensitive to seed extract with a MIC of 1366.25 mg/mL and a MFC of 2672.5 mg/mL, which allows recommending the development of effective pharmacological formulations for the control of candidiasis.

Pituitary Apoplexy: Description of Medical and Surgical Treatment and Clinical, Visual, and Endocrinological Outcomes During the SARS-CoV-2 Pandemic and Over Three Years.

INTRODUCTION: Pituitary apoplexy (PA) is a rare neuroendocrinological emergency. The SARS-CoV-2 pandemic recommendations led to a shift in the management of patients with pituitary diseases, especially in the decision-making between conservative and surgical treatment of patients with PA. OBJECTIVE: This study aimed to describe the conservative and surgical treatment and the clinical, visual, and endocrinological outcomes in patients with PA at the Pituitary Center of Excellence (PTCEO) during the SARS-CoV-2 pandemic and within three years. METHODS: This is a cohort study. Patients with PA between April 2020 and September 2023 were followed up. Treatment decisions, clinical manifestations, hormonal profile, and tumor size with MRI were described at the onset, at three months, six months, one year, two years, and three years after diagnosis. RESULTS: A total of 27 patients with PA diagnosis were included in the study. Of these, 12 patients were conservatively treated, six (50%) had prolactinomas, five (41.6%) had non-functioning adenomas, and one (8.3%) had pituicytoma. Fifteen patients were surgically intervened during the first hospitalization, nine (60%) had non-functioning adenomas, four (26.6%) had prolactinomas, one (6.6%) had ACTH-producing adenoma, and one (6.6%) had gonadotropinoma. Two patients from the conservatively treated group (one non-functioning adenoma and one pituicytoma) were intervened surgically at years 2 and 3, respectively. During the initial assessment, there were no statistically significant differences between patients in visual acuity (9 [75%] vs 15 [100%]), visual field affection (8 [66.6%] vs 11 [73.3%]), and cranial nerve deficit (3 [25%] vs 6 [40%]). At six months follow-up, no statistically significant differences were found in the visual acuity improvement (8 [88%] vs 11 [100%]), visual field (8 [100%] vs 8 [72%]), and cranial nerve deficit between the two groups (3 [100%] vs 6 [100%]). Meanwhile, the average length of in-hospital stay was 1.5 vs 10 days (p = 0.019). The tumor size and largest diameter were smaller in the surgically treated group (6.2 vs. 0.5 cm3, p = 0.029 and 2.5 vs. 1.1 cm, p = 0.036, respectively). Visual acuity improved in nine (58.3%) patients at year 1: two (40%) conservative vs seven (100%) surgical (p = 0.039); six (85.7%) patients at year 2: two (66.6%) conservative vs. four (100%) surgical; and three (100%) patients on both groups at year 3. Fourteen patients needed hormonal substitution: 87.5% (eight [88.8%] conservative vs six [85.7%] surgical) at year 1, 85.7% (six patients in both groups) at year 2, and 80% (four conservative vs three [100%] surgical) at year 3. The thyrotropic axis was the most affected in both groups during the three years. During the first-year follow-up, six (85%) patients persisted with tumoral regression (2 [66.6%] conservative vs 4 [100%] surgical) and one (14.2%) patient from the medical group progressed. During the second and third years, 10 and three (100%) of the patients, respectively, showed the regression of the tumoral volume in both groups. CONCLUSIONS: The clinical, visual, and neuroendocrinological outcomes were similar in both groups of patients with PA during the SARS-CoV-2 pandemic. In cases where the Pituitary Apoplexy Score (PAS) score does not surpass three points without neurological deterioration, conservative management can be considered an adequate option for treatment.

The protective effect of 1400W against ischaemia and reperfusion injury is countered by transient medullary kidney endothelial dysregulation.

Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition.

Insecticide Efficacy of Green Synthesis Silver Nanoparticles on Diaphorina citri Kuwayama (Hemiptera: Liviidae).

Diaphorina citri Kuwayama (Hemiptera: Liviidae) is a vector of Liberibacter asiaticus Jagoueix et al. and Liberibacter americanus Teixeira et al., causal agents of the critical yellow dragon disease or Huanglongbing (HLB), which affects citrus production worldwide. Recently, green synthetic nanoparticles have emerged as a potential alternative to control of agricultural insect pests. The insecticide effect of silver nanoparticles (AgNPs) on 2nd instar nymphs of D. citri under laboratory and greenhouse conditions was evaluated. Mortality was recorded 24, 48, and 72 h after application on D. citri nymphs under both laboratory and greenhouse conditions. The laboratory results showed that AgNPs caused 97.84 and 100% mortality at 32 and 64 ppm, respectively, 72 h after treatment. In the greenhouse, AgNPs caused 78.69 and 80.14% mortality using 64 and 128 ppm 72 h after application. This research is the first to evaluate the green synthesis AgNPs on D. citri and are a promising strategy to control the pest.

Rare histological prostate cancer subtypes: Cancer-specific and other-cause mortality.

BACKGROUND: To assess cancer-specific mortality (CSM) and other-cause mortality (OCM) rates in patients with rare histological prostate cancer subtypes. METHODS: Using the Surveillance, Epidemiology, and End Results database (2004-2020), we applied smoothed cumulative incidence plots and competing risks regression (CRR) models. RESULTS: Of 827,549 patients, 1510 (0.18%) harbored ductal, 952 (0.12%) neuroendocrine, 462 (0.06%) mucinous, and 95 (0.01%) signet ring cell carcinoma. In the localized stage, five-year CSM vs. OCM rates ranged from 2 vs. 10% in acinar and 3 vs. 8% in mucinous, to 55 vs. 19% in neuroendocrine carcinoma patients. In the locally advanced stage, five-year CSM vs. OCM rates ranged from 5 vs. 6% in acinar, to 14 vs. 16% in ductal, and to 71 vs. 15% in neuroendocrine carcinoma patients. In the metastatic stage, five-year CSM vs. OCM rates ranged from 49 vs. 15% in signet ring cell and 56 vs. 16% in mucinous, to 63 vs. 9% in ductal and 85 vs. 12% in neuroendocrine carcinoma. In multivariable CRR, localized neuroendocrine (HR 3.09), locally advanced neuroendocrine (HR 9.66), locally advanced ductal (HR 2.26), and finally metastatic neuroendocrine carcinoma patients (HR 3.57; all p < 0.001) exhibited higher CSM rates relative to acinar adenocarcinoma patients. CONCLUSIONS: Compared to acinar adenocarcinoma, patients with neuroendocrine carcinoma of all stages and locally advanced ductal carcinoma exhibit higher CSM rates. Conversely, CSM rates of mucinous and signet ring cell adenocarcinoma do not differ from those of acinar adenocarcinoma.

Prognostic value of surgical resection over biopsy in elderly patients with glioblastoma: a meta-analysis.

PURPOSE: Maximal-safe resection has been shown to improve overall survival in elderly patients with glioblastoma in observational studies, however, the only clinical trial comparing resection versus biopsy in elderly patients with surgically-accessible glioblastoma showed no improvements in overall survival. A meta-analysis is needed to assess whether surgical resection of glioblastoma in older patients improves surgical outcomes when compared to biopsy alone. METHODS: A search was conducted until October 9th, 2023, to identify published studies reporting the clinical outcomes of glioblastoma patients > 65 years undergoing resection or biopsy (PubMed, MEDLINE, EMBASE, and COCHRANE). Primary outcomes were overall survival (OS), progression-free survival (PFS), and complications. We analyzed mean difference (MD) and hazard ratio (HR) for survival outcomes. Postoperative complications were analyzed as a dichotomic categorical variable with risk ratio (RR). RESULTS: From 784 articles, 20 cohort studies and 1 randomized controlled trial met our inclusion criteria, considering 20,523 patients for analysis. Patients undergoing surgical resection had an overall survival MD of 6.13 months (CI 95%=2.43-9.82, p = < 0.001) with a HR of 0.43 (95% CI = 0.35-0.52, p = < 0.00001). The progression-free survival MD was 2.34 months (95%CI = 0.79-3.89, p = 0.003) with a 0.50 h favoring resection (95%CI = 0.37-0.68, p = < 0.00001). The complication RR was higher in the resection group favoring biopsy (1.49, 95%CI = 1.06-2.10). CONCLUSIONS: Our meta-analysis suggests that upfront resection is associated with improved overall survival and progression-free survival in elderly patients with newly diagnosed glioblastoma over biopsy. However, postoperative complications are more common with resection. Future clinical trials are essential to provide more robust evaluation in this challenging patient population.

Impact of Neoadjuvant Treatment on Body Composition in Patients with Locally Advanced Gastric Cancer.

Neoadjuvant chemotherapy (NT) followed by radical surgery is the standard treatment for locally advanced gastric cancer (GC). The incidence of sarcopenia in upper gastrointestinal tract malignancies is very high, and it may be increased after NT. This study aimed to evaluate the impact of NT on body composition. A retrospective study of patients with locally advanced GC undergoing gastrectomy who had received NT in a tertiary hospital between 2012 and 2019 was conducted. CT measured the skeletal muscle index, total psoas area, and visceral and subcutaneous adipose tissue before and after NT. Of the 180 gastrectomies for GC, 61 patients received NT. During NT, changes in body composition were observed with a decrease in the skeletal muscle mass index (SMMI -2.5%; p < 0.001), and these changes were significantly greater in men (SMMI -10.55%). Before surgery, patients who received NT presented 15% more sarcopenia than those without NT (p = 0.048). In conclusion, patients with locally advanced gastric cancer who receive NT have significant changes in body composition during chemotherapy. These changes, which are at the expense of a loss of muscle mass, lead to an increased incidence of pre-surgical sarcopenia.

Measurement of left ventricular volume with admittance incorporated onto percutaneous ventricular assist device.

Percutaneous ventricular assist devices (pVADs) incorporated with admittance electrodes have been validated in animal studies for accurate instantaneous volumetric measurements. Since miniaturization of the pVAD profile is a priority to reduce vascular complications in patients, our study aimed to validate admittance measurements using three electrodes instead of the standard four. Complex admittance was measured between an electrode pair and a pVAD metallic blood-intake tip, both with finite element analysis and on the benchtop. The catheter and electrode arrays were first simulated inside prolate ellipsoid models of the left ventricle (LV) demonstrating current flow throughout all parts of the LV as well as minimal influence of off-center catheter placement in the recorded signal. Admittance measurements were validated in 3D-printed models of healthy and dilated hearts (100-400 mL end-diastolic volumes). Minimal interference between a pVAD motor and the current signal of our admittance system was demonstrated. A modified Wei's equation focused on three electrodes was developed to be compatible with reduced profile pVADs occurring clinically, incorporated with admittance electrodes and wires. The modified equation was compared against Wei's original equation showing improved accuracy of calculated volumes. Reducing electrode footprint can simplify the incorporation of Admittance technology on any pVAD, allowing for instantaneous recognition of native heart recovery and assistance with pVAD weaning.

Hepatocellular Carcinoma in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Importance: In the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC. Objective: To develop a prediction model for HCC incidence in a cohort of patients with MASLD. Design, Setting, and Participants: This prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024. Exposure: Data were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD. Main Outcome and Measures: The cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk. Results: A total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241. Conclusions and Relevance: This prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.

The type III effector NopL interacts with GmREM1a and GmNFR5 to promote symbiosis in soybean.

The establishment of symbiotic interactions between leguminous plants and rhizobia requires complex cellular programming activated by Rhizobium Nod factors (NFs) as well as type III effector (T3E)-mediated symbiotic signaling. However, the mechanisms by which different signals jointly affect symbiosis are still unclear. Here we describe the mechanisms mediating the cross-talk between the broad host range rhizobia Sinorhizobium fredii HH103 T3E Nodulation Outer Protein L (NopL) effector and NF signaling in soybean. NopL physically interacts with the Glycine max Remorin 1a (GmREM1a) and the NFs receptor NFR5 (GmNFR5) and promotes GmNFR5 recruitment by GmREM1a. Furthermore, NopL and NF influence the expression of GmRINRK1, a receptor-like kinase (LRR-RLK) ortholog of the Lotus RINRK1, that mediates NF signaling. Taken together, our work indicates that S. fredii NopL can interact with the NF signaling cascade components to promote the symbiotic interaction in soybean.

Association between Helicobacter pylori infection, mismatch repair, HER2 and tumor-infiltrating lymphocytes in gastric cancer.

BACKGROUND: The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information. AIM: To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC. METHODS: Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 immune cells, and dMMR and HER2-status were determined by immunohistochemistry (IHC). H. pylori infection was evaluated by routine histology and quantitative PCR (qPCR) in a subset of samples. RESULTS: dMMR was found in 34.4%, HER2+ in 5% and H. pylori-positive in 55.7% of samples. High IT-TIL was associated with grade-3 (P = 0.038), while ST-TIL with grade-1 (P < 0.001), intestinal-histology (P < 0.001) and no-recurrence (P = 0.003). dMMR was associated with high TIL levels in the ST (P = 0.019) and IB (P = 0.01) compartments, and ST-CD3 (P = 0.049) and ST-CD8 (P = 0.05) densities. HER2- was associated with high IT-CD8 (P = 0.009). H. pylori-negative was associated with high IT-TIL levels (P = 0.009) when assessed by routine-histology, and with high TIL levels in the 3 compartments (P = 0.002-0.047) and CD8 density in the IT and ST compartments (P = 0.001) when assessed by qPCR. A longer overall survival was associated with low IT-CD163 (P = 0.003) and CD8/CD3 (P = 0.001 in IT and P = 0.002 in ST) and high IT-CD3 (P = 0.021), ST-CD3 (P = 0.003) and CD3/CD163 (P = 0.002). CONCLUSION: TIL levels were related to dMMR and H. pylori-negativity. Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions.

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins' preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

Performance of the First-Trimester Cervical Consistency Index to Predict Preterm Birth.

Background/Objectives: Preterm birth (PTB) remains a significant global health challenge. Previous attempts to predict preterm birth in the first trimester using cervical length have been contradictory. The cervical consistency index (CCI) was introduced to quantify early cervical changes and has shown promise across various clinical scenarios in the mid-trimester, though testing in the first trimester is lacking. This study aims to assess the cervical consistency index performance in predicting preterm birth during the first trimester of pregnancy. Methods: In this prospective cohort study, focused exclusively on research, women with singleton pregnancies, both with and without a history of spontaneous preterm birth (sPTB), were included. The primary outcome was sPTB before 37 weeks, with a secondary outcome of sPTB before 34 weeks. CCI measurements were taken between 11+0 to 13+6 weeks of gestation. Receiver operating characteristic (ROC) curves were generated, and sensitivity and specificity were calculated for the optimal cut-off and for the 5th, 10th, and 15th percentile. Intraobserver and interobserver agreements were assessed using the intraclass correlation coefficient (ICC). Results: Among the 667 patients analyzed, the rates of sPTB before 37 and 34 weeks were 9.2% (61/667) and 1.8% (12/667), respectively. The detection rates (DRs) for CCI predicting PTB before 37 and 34 weeks were 19.7% (12/61) and 33.3% (4/12). Negative predictive values were 91.8% (546/595) and 98.7% (588/596), while the areas under the curve (AUC) for sPTB before 37 and 34 weeks were 0.62 (95% CI: 0.54-0.69) and 0.80 (95% CI: 0.71-0.89), respectively. Of the 61 patients with preterm birth, 13 (21.3%) had a preterm birth history; in this group, the CCI percentile 10th identified 39% (5/13). Intraobserver ICC was 0.862 (95% CI: 0.769-0.920), and interobserver ICC was 0.833 (95% CI: 0.722-0.902). Conclusions: This study suggests that utilizing CCI in the first trimester of pregnancy could serve as a valuable tool for predicting preterm birth before 34 weeks of gestation, demonstrating robust intraobserver and interobserver reliability.

Mesenchymal Stem Cells and Their Derived Products in Ageing and Diseases.

Despite the enormous efforts of the pharmaceutical industry in the generation of new drugs (55 new ones last year) [...].