Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis.

The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA-atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA-atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA.

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

Analysis of the Associations of Measurements of Body Composition and Inflammatory Factors with Cardiovascular Disease and Its Comorbidities in a Community-Based Study.

The associations of cardiovascular disease (CVD) with comorbidities and biochemical and body composition measurements are repeatedly described but have not been studied simultaneously. In the present cross-sectional study, information on CVD and comorbidities [type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HDL)], body composition, levels of soluble markers, and other measures were collected from 1079 individuals. When we examined the association of each comorbidity and CVD, controlling for other comorbidities, we observed a clear pattern of the comorbidity-related specific associations with tested covariates. For example, T2DM was significantly associated with GDF-15 levels and the leptin/adiponectin (L/A) ratio independently of two other comorbidities; HTN, similarly, was independently associated with extracellular water (ECW) levels, L/A ratio, and age; and HDL was independently related to age only. CVD showed very strong independent associations with each of the comorbidities, being associated most strongly with HTN (OR = 10.89, 6.46-18.38) but also with HDL (2.49, 1.43-4.33) and T2DM (1.93, 1.12-3.33). An additive Bayesian network analysis suggests that all three comorbidities, particularly HTN, GDF-15 levels, and ECW content, likely have a main role in the risk of CVD development. Other factors, L/A ratio, lymphocyte count, and the systemic inflammation response index, are likely indirectly related to CVD, acting through the comorbidities and ECW.

Assessing the efficacy of 2D and 3D CNN algorithms in OCT-based glaucoma detection.

Glaucoma is a progressive neurodegenerative disease characterized by the gradual degeneration of retinal ganglion cells, leading to irreversible blindness worldwide. Therefore, timely and accurate diagnosis of glaucoma is crucial, enabling early intervention and facilitating effective disease management to mitigate further vision deterioration. The advent of optical coherence tomography (OCT) has marked a transformative era in ophthalmology, offering detailed visualization of the macula and optic nerve head (ONH) regions. In recent years, both 2D and 3D convolutional neural network (CNN) algorithms have been applied to OCT image analysis. While 2D CNNs rely on post-prediction aggregation of all B-scans within OCT volumes, 3D CNNs allow for direct glaucoma prediction from the OCT data. However, in the absence of extensively pre-trained 3D models, the comparative efficacy of 2D and 3D-CNN algorithms in detecting glaucoma from volumetric OCT images remains unclear. Therefore, this study explores the efficacy of glaucoma detection through volumetric OCT images using select state-of-the-art (SOTA) 2D-CNN models, 3D adaptations of these 2D-CNN models with specific weight transfer techniques, and a custom 5-layer 3D-CNN-Encoder algorithm. The performance across two distinct datasets is evaluated, each focusing on the macula and the ONH, to provide a comprehensive understanding of the models' capabilities in identifying glaucoma. Our findings demonstrate that the 2D-CNN algorithm consistently provided robust results compared to their 3D counterparts tested in this study for glaucoma detection, achieving AUC values of 0.960 and 0.943 for the macular and ONH OCT test images, respectively. Given the scarcity of pre-trained 3D models trained on extensive datasets, this comparative analysis underscores the overall utility of 2D and 3D-CNN algorithms in advancing glaucoma diagnostic systems in ophthalmology and highlights the potential of 2D algorithms for volumetric OCT image-based glaucoma detection.

Functional outcomes of diets in multiple sclerosis (FOOD for MS): Protocol for a parallel arm randomized feeding trial for low glycemic load and calorie restriction.

BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (n = 50) or a standard GL diet (n = 50). Both diet groups will complete two study phases: a eucaloric phase (16 weeks) and a CR phase (16 weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.

Rbpj deletion in hepatic progenitor cells attenuates endothelial responses in a mouse model of cholestatic liver disease.

Background and Aims: Since the role of hepatic progenitor cells (HPCs) constituting ductular reactions in pathogenesis remains ambiguous, we aimed to establish the in vivo cause-and-effect relationship between HPCs and angiogenesis, a process associated with chronic liver disease progression. We previously demonstrated that peritumoral ductules are associated with angiogenesis in liver tumors and forkhead box L1 (Foxl1)- expressing murine HPCs secrete angiogenic factors in vitro. Therefore, we hypothesized that HPCs are capable of remodeling the vascular microenvironment and this function of HPCs is dependent on recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a key effector of the Notch signaling pathway. Approach and Results: We generated HPC-specific Rbpj conditional knockout mice using Foxl1-Cre and treated them with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet to induce cholestatic liver disease. Knockout mice displayed significant reduction of HPC proliferation and ductular reactions as well as attenuated vascular and fibrotic areas compared to control mice. Assessment of vascular endothelial growth factor A-positive areas in vivo and the effects of Rbpj shRNAs in vitro indicated that Rbpj knockout in HPCs reduces the total number of angiogenic factor-expressing cells rather than affecting angiogenic factor expression within HPCs. Single-nucleus RNA sequencing analysis indicated that conditional Rbpj knockout in HPCs induces transcriptional changes in endothelial cells and alters expression of genes involved in various functions of the endothelium. Conclusion: Our findings indicate that HPCs regulate endothelial responses to cholestatic liver disease and Rbpj deletion in HPCs attenuates these responses, identifying novel targets for modulating angiogenesis during disease progression.

BiliQML: a supervised machine-learning model to quantify biliary forms from digitized whole slide liver histopathological images.

The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed, error prone, and lack architectural context or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine-learning model (BiliQML) able to quantify biliary forms in the liver of anti-keratin 19 antibody-stained whole slide images. Training utilized 5,019 researcher-labeled biliary forms, which following feature selection, and algorithm optimization, generated an F score of 0.87. Application of BiliQML on seven separate cholangiopathy models [genetic (Afp-CRE;Pkd1l1null/Fl, Alb-CRE;Rbp-jkfl/fl, and Albumin-CRE;ROSANICD), surgical (bile duct ligation), toxicological (3,5-diethoxycarbonyl-1,4-dihydrocollidine), and therapeutic (Cyp2c70-/- with ileal bile acid transporter inhibition)] allowed for a means to validate the capabilities and utility of this platform. The results from BiliQML quantification revealed biological and pathological differences across these seven diverse models, indicating a highly sensitive, robust, and scalable methodology for the quantification of distinct biliary forms. BiliQML is the first comprehensive machine-learning platform for biliary form analysis, adding much-needed morphologic context to standard immunofluorescence-based histology, and provides clinical and basic science researchers with a novel tool for the characterization of cholangiopathies.NEW & NOTEWORTHY BiliQML is the first comprehensive machine-learning platform for biliary form analysis in whole slide histopathological images. This platform provides clinical and basic science researchers with a novel tool for the improved quantification and characterization of biliary tract disorders.

The Role of Pharmaceutical Innovation in Clinical Practice Guidelines for Chronic Diseases.

Background: Over the last 25 years, clinical practice guidelines have emerged as a means to standardize and improve care. As pharmaceutical innovations develop, guidelines are updated to incorporate new interventions. However, the extent to which pharmacotherapies are represented as treatment options in guideline recommendations has not been well elucidated. This study aimed to quantify the role pharmacotherapy has played in clinical practice guidelines across a range of chronic diseases over the past 20 years. Methods: Clinical practice guidelines published from 2000 to 2021 were identified for five chronic diseases: ischemic heart disease (IHD), non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), Alzheimer's disease (AD), and type 2 diabetes (T2D). Guidelines were reviewed and data on treatment recommendations were collected, including the type of intervention, line of therapy, and, for pharmacotherapies, year of regulatory approval and year of inclusion in guidelines. Results: In total, 92 clinical practice guidelines were reviewed. Among the 184 discrete recommended interventions across the five disease areas, 146 (79.3%) were pharmacotherapies, 21 (11.4%) were behavioral modifications, 6 (3.3%) were surgical interventions, and 11 (6%) were other interventions. Across guidelines, when a line of therapy was specified, behavioral modifications and pharmacotherapies were most frequently recommended as first-line interventions, whereas surgical interventions were more often recommended for subsequent lines of treatment. The time from regulatory approval of novel pharmacotherapies to inclusion in guideline recommendations varied considerably by disease area and geography. Conclusions: Across the reviewed disease areas, behavioral interventions and pharmacotherapies are shown to be critical components of clinical practice. Over the last 20 years, novel pharmaceutical innovations have been incorporated into clinical practice guideline recommendations; however, with varying speeds of adoption. Given the increasing pace of pharmacologic innovation, timely updates of clinical practice guidelines are critical to evolving the standard of care and practicing evidence-based medicine.

High-speed, phase contrast retinal and blood flow imaging using an adaptive optics partially confocal multi-line ophthalmoscope.

High-speed, phase contrast retinal and blood flow imaging using an adaptive optics partially confocal multi-line ophthalmosocope (AO-pcMLO) is described. It allows for simultaneous confocal and phase contrast imaging with various directional multi-line illumination by using a single 2D camera and a digital micromirror device (DMD). Both vertical and horizontal line illumination directions were tested, for photoreceptor and vascular imaging. The phase contrast imaging provided improved visualization of retinal structures such as cone inner segments, vessel walls and red blood cells with images being acquired at frame rates up to 500 Hz. Blood flow velocities of small vessels (<40 µm in diameter) were measured using kymographs for capillaries and cross-correlation between subsequent images for arterioles or venules. Cardiac-related pulsatile patterns were observed with normal resting heart-beat rate, and instantaneous blood flow velocities from 0.7 to 20 mm/s were measured.

Comparing Intramedullary Nails and Locking Plates in Displaced Proximal Humerus Fracture Management: A Systematic Review and Meta-Analysis.

This study aims to provide an updated review comparing the complication rates and clinical outcomes of intramedullary nails and locking plates (LPs) in displaced proximal humerus fracture (PHF) management. We performed a systematic review of the Cochrane Central Register of Controlled Trials, Clinical Trials Registry, EMBASE, and PubMed. Studies with level III evidence or higher comparing intramedullary nails and LPs used for internal fixation of displaced PHFs were included. The Methodological Index for Nonrandomized Studies (MINORS) criteria and Cochrane Handbook for Systematic Reviews of Interventions 5.2.0 were used to assess the risk of bias. Our meta-analysis included a comparison of method-related complications, pain scores, range of motion (ROM), and functional scores. A total of 13 comparative studies were included: five randomized controlled trials, three prospective cohort studies, and five retrospective cohort studies. The total number of patients included was 1,253 (677 in the LP group and 576 in the intramedullary nail group). Superior Constant-Murley scores and external rotation ROM were found in the LP group during the early postoperative period. However, long-term functional scores and complication rates were comparable between the two groups. We conclude that intramedullary nailing and LP fixation are both equally effective for the treatment of displaced PHFs. Neither treatment appears superior at this time, and more large-scale randomized controlled trials should be conducted to further evaluate the potential benefit of LPs in the early postoperative period.

Quantitative Analysis of the Vasculature and Cone Photoreceptors in Subjects With Diabetes Without Diabetic Retinopathy.

PURPOSE: To characterize any differences in the vasculature and cone photoreceptor packing geometry (CPG) between subjects with diabetes without/no diabetic retinopathy (NDR) and healthy controls. METHODS: Eight NDR and five controls were enrolled. Optical coherence tomography angiography (OCTA) taken at the macula was used to measure vessel density, vessel length density, and vessel density index (VDI) in three vascular plexuses, namely, the superficial vascular plexus, intermediate capillary plexus, and deep capillary plexus (DCP). The choriocapillaris (CC) flow deficit (FD) was also measured. OCTA images were binarized and processed to extrapolate the parafovea and parafoveal quadrants and the OCTA indices mentioned above. The CC was processed with six different radii to quantify FD. Adaptive optics - scanning laser ophthalmoscopy images were acquired and processed to extract CPG indices, i.e., cone density (CD), cone-to-cone spacing (CS), linear dispersion index, heterogeneity packing index and percent of cells with six neighbors at 3.6° in the temporal retina. RESULTS: In all eyes, statistically significant differences were found (i) in parafoveal FD across the six radii (p < 0.001) and (ii) in the correlation between the parafoveal temporal quadrant (PTQ) DCP VDI and CS (r = 0.606, p = 0.048). No other significant correlations were found. For OCTA or CPG indices, no significant differences were found between the cohorts in the parafovea or parafoveal quadrants. CONCLUSIONS: CS is the most sensitive CPG index for detecting alterations in the cone mosaic. The DCP and the cone photoreceptors are significantly correlated, indicating that alterations in the DCP can affect the cones. Future work elucidating the vascular alterations and neurodegeneration present in diabetic eyes should focus on the DCP and multiple CPG indices, not solely CD. Moreover, such alterations are highly localized, hence using larger regions e.g. parafovea versus smaller areas, such as the PTQ, will potentially mask significant correlations.

Youth Exposure to Recreational Cannabis Legalization: Moderation of Effects by Sex and Parental Cannabis Use during Adolescence.

OBJECTIVE: Few studies of recreational cannabis legalization (RCL) have assessed adolescents both before and after RCL or considered moderators of RCL effects. The present study tested whether RCL was more strongly associated with cannabis use for girls and among youth whose parents had a history of cannabis use during adolescence. METHOD: Data were pooled from 940 adolescents from three intergenerational studies that began in Washington (where RCL was enacted in 2012), Oregon (RCL year = 2015), and New York (RCL year = 2021). Youth were assessed repeatedly from ages 13 to 18 years (k = 3,650 person-years) from 1999 to 2020 (prior to RCL in New York). Parent cannabis use at or before age 18 years (yes/no) was assessed prospectively during the parent's adolescence. Multilevel models focused on the between-subjects effects of years of youth exposure to RCL on adolescents' mean cannabis use likelihood, and interactions with child sex and parent use history. RESULTS: Child exposure to RCL was associated with a higher likelihood of cannabis use if their parents had a history of adolescent use, (Estimate [SE] = 0.67 [0.25], p = 0.008), versus no such history (Estimate [SE] = -0.05 [0.28], p = 0.855). RCL effects were not moderated by child sex. CONCLUSIONS: The effects of RCL on adolescents' cannabis use may depend on their parents' history of using the drug. Identifying other moderators of RCL effects, and understanding the mechanisms of these risks and the ways that parents and communities can offset them, are prevention priorities.

(1) Adolescents' use of cannabis may have intergenerational consequences, making it more likely their future offspring will use cannabis. (2) Whether or not recreational cannabis legalization influences adolescents' cannabis use may depend on their parents' cannabis use history. (3) Parenting in a state with liberalized cannabis policies may present new challenges and require that novel prevention resources be developed.

Relationships between Circulating Biomarkers and Body Composition Parameters in Patients with Metabolic Syndrome: A Community-Based Study.

Metabolic syndrome (MetS) is a complex disease involving multiple physiological, biochemical, and metabolic abnormalities. The search for reliable biomarkers may help to better elucidate its pathogenesis and develop new preventive and therapeutic strategies. In the present population-based study, we looked for biomarkers of MetS among obesity- and inflammation-related circulating factors and body composition parameters in 1079 individuals (with age range between 18 and 80) belonging to an ethnically homogeneous population. Plasma levels of soluble markers were measured by using ELISA. Body composition parameters were assessed using bioimpedance analysis (BIA). Statistical analysis, including mixed-effects regression, with MetS as a dependent variable, revealed that the most significant independent variables were mainly adipose tissue-related phenotypes, including fat mass/weight (FM/WT) [OR (95% CI)], 2.77 (2.01-3.81); leptin/adiponectin ratio (L/A ratio), 1.50 (1.23-1.83); growth and differentiation factor 15 (GDF-15) levels, 1.32 (1.08-1.62); inflammatory markers, specifically monocyte to high-density lipoprotein cholesterol ratio (MHR), 2.53 (2.00-3.15), and a few others. Additive Bayesian network modeling suggests that age, sex, MHR, and FM/WT are directly associated with MetS and probably affect its manifestation. Additionally, MetS may be causing the GDF-15 and L/A ratio. Our novel findings suggest the existence of complex, age-related, and possibly hierarchical relationships between MetS and factors associated with obesity.

Screening, Diagnosis, and Initial Care of Asian and White Patients With Lung Cancer.

BACKGROUND: Data on the care of Asian patients with lung cancer in the US are limited; however, lung cancer is the leading cause of cancer death in this population. METHODS: Demographics, low-dose computed tomography (LDCT) screening, disease characteristics, and treatment history were compared between Asian and White patients newly diagnosed with lung cancer from 2014 to 2019 identified from Tufts Medical Center cancer registry. The influence of race on presenting stage was assessed via ordinal logistic regression. Time to treatment initiation (TTI) and overall survival (OS) were analyzed via log-rank tests. The impact of race on OS was evaluated via multivariable Cox regression. RESULTS: Asian patients (N = 144) were more likely to prefer non-English languages, use interpreters, be never-smokers, and harbor EGFR alterations, compared to White patients (N = 472), and to be diagnosed with later-stage lung cancer (odds ratio: 2.14, P < .001), had longer median TTI (early stage: 2.30 vs. 1.43 months, P = .035; curative stage: 1.88 vs. 1.20 months, P = .041) and more often did not receive cancer-directed therapy (12.6% vs. 5.7%, P = .01). Screening LDCT was done only in 11.9% of Asian and 21.4% of White patients (P = .20) who would have met screening criteria prior to diagnosis (N = 215). Median OS was similar between Asian and White patients (not reached vs. 74.8 months, P = .17). Multivariable Cox model suggested better OS for Asian patients (hazard ratio: 0.57, P = .01). CONCLUSION: In our study, Asian patients presented with later-stage lung cancer, had treatment delays, and more often did not receive treatment, compared to White patients, yet did not have inferior survival.

Reducing Suicidal Ideation in Preadolescents With a History of Foster Care by Promoting School Readiness in Early Childhood.

Preadolescents with a history of foster care placement report suicidal ideation (SI) at higher rates than their peers, which increases their risk for suicide attempts in adolescence. Despite these increased risks, few interventions have been shown to reduce SI in these youth. This study examined the main and mediated long-term effects of a program to increase school readiness in children in foster care at age 5 years on SI when the children were ages 9-11 years, 4-6 years after the intervention ended. Children who received the intervention were less likely to report SI, although the difference did not reach statistical significance. The intervention reduced SI indirectly through its positive effect on children's self-esteem at age 9 years. Implications for programming to reduce SI and subsequent suicide attempts in youth with a history of foster care are discussed.

Foveal cone loss in tamoxifen maculopathy: a case report.

BACKGROUND: Tamoxifen is used in low dose concentrations (20-40 mg per day) as a therapy for breast cancer but is known to have ocular side effects. In this case report, the foveal cone integrity in a tamoxifen-treated patient who complained of a small central scotoma in the left eye while reading was examined using high resolution adaptive optics imaging. CASE PRESENTATION: Both eyes of a 54-year-old Caucasian, non-hispanic female who had been treated with tamoxifen for 1.5 years were examined using various imaging modalities including fundus photography, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy. Clinical spectral-domain optical coherence tomography showed a very small disruption to the photoreceptor layer at the fovea in the left eye only. However, adaptive optics scanning laser ophthalmoscopy imaging revealed foveal cone loss in both eyes, but to a lesser extent in the right eye. Inner retinal changes were not observed in either eye. CONCLUSION: The area of cone loss was similar in size to a single newsprint letter when projected onto the retina, matching the patient's description of a scotoma in the left eye. Given the isolated loss of foveal cone photoreceptors with the absence of previously reported inner retinal and vascular changes, our results may indicate the earliest retinal changes associated with tamoxifen retinopathy.

The Co-Occurrence of Conduct Problems and Depressive Symptoms From Childhood to Adulthood for Men: Stability Over Time and Prediction to Substance Use.

The dual pathway hypothesis of risk for substance use was tested by examining risk from symptoms of conduct problems and depressive symptoms in adolescence (from ages 10-11 to 17-18 years) to substance use-including tobacco, alcohol, cannabis, and other illicit drugs-in both early adulthood (approximately from ages 20 to 29 years) and middle adulthood (approximately from ages 29 to 38 years). Hypotheses were tested on a sample of boys who were at risk for conduct problems by virtue of the neighborhoods where they lived in childhood (the Oregon Youth Study; N = 206 at Wave 1). Dual-trajectory modeling (Latent Class Analysis) resulted in a 3-group solution of high, moderate, and low co-occurring symptoms. The latent class of boys with co-occurring symptoms in adolescence showed higher levels of substance use in adulthood; namely, higher levels of cannabis and illicit substance use during early adulthood compared to either of the moderate or low symptom classes, and higher use of cannabis in midadulthood than the low symptom class. Those with co-occurring symptoms also showed, overall, higher vulnerability to use of tobacco in these 2 periods, but not to higher use of alcohol. Regression analyses indicated that the higher substance use of the co-occur group of men was related to their adolescent conduct problems, but was not related to their adolescent depressive symptoms; however, these associations were nonsignificant when adolescent use of the respective substances were included in the models. Thus, the dual-trajectory hypothesis was not supported. However, the findings indicated that, as assessed in the present study, the psychopathology symptoms of boys with conduct problems in adolescence who show risk for later substance use may be complex, involving depressive symptoms.

SLAMF7 as a Promising Immunotherapeutic Target in Multiple Myeloma Treatments.

Multiple myeloma (MM) is a common hematological malignancy that has fostered several new therapeutic approaches to combat newly diagnosed or relapsed MM. While the field has advanced over the past 2 decades, the majority of patients will develop resistance to these treatments, causing the need for new therapeutic targets. SLAMF7 is an attractive therapeutic target in multiple myeloma, and a monoclonal antibody that targets SLAMF7 has shown consistent beneficial outcomes in clinical trials to date. In this review, we will focus on the structure and regulation of SLAMF7 and its mechanism of action. The most recent clinical trials will be reviewed to further understand the clinical implications and improve the prognosis of MM. Furthermore, the efficacy of anti-SLAMF7 monoclonal antibodies combined with standard therapies and possible resistance mechanisms will be discussed. This review aimed to provide a detailed summary of the role of SLAMF7 in the pathogenesis of patients with MM and the rationale for further investigation into SLAMF7-mediated molecular pathways associated with MM development.

Single-cell sequencing reveals the landscape of the human brain metastatic microenvironment.

Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It is a leading cause of death in advanced-stage cancer, resulting in a five-year overall survival rate below 10%. Therefore, there is a critical need to identify effective biomarkers that can support frequent surveillance and promote efficient drug guidance in brain metastasis. Recently, the remarkable breakthroughs in single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into the tumor microenvironment (TME) at single-cell resolution, which offers the potential to unravel the metastasis-related cellular crosstalk and provides the potential for improving therapeutic effects mediated by multifaceted cellular interactions within TME. In this study, we have applied scRNA-seq and profiled 10,896 cells collected from five brain tumor tissue samples originating from breast and lung cancers. Our analysis reveals the presence of various intratumoral components, including tumor cells, fibroblasts, myeloid cells, stromal cells expressing neural stem cell markers, as well as minor populations of oligodendrocytes and T cells. Interestingly, distinct cellular compositions are observed across different samples, indicating the influence of diverse cellular interactions on the infiltration patterns within the TME. Importantly, we identify tumor-associated fibroblasts in both our in-house dataset and external scRNA-seq datasets. These fibroblasts exhibit high expression of type I collagen genes, dominate cell-cell interactions within the TME via the type I collagen signaling axis, and facilitate the remodeling of the TME to a collagen-I-rich extracellular matrix similar to the original TME at primary sites. Additionally, we observe M1 activation in native microglial cells and infiltrated macrophages, which may contribute to a proinflammatory TME and the upregulation of collagen type I expression in fibroblasts. Furthermore, tumor cell-specific receptors exhibit a significant association with patient survival in both brain metastasis and native glioblastoma cases. Taken together, our comprehensive analyses identify type I collagen-secreting tumor-associated fibroblasts as key mediators in metastatic brain tumors and uncover tumor receptors that are potentially associated with patient survival. These discoveries provide potential biomarkers for effective therapeutic targets and intervention strategies.

Bayesian network modeling of patterns of antibiotic cross-resistance by bacterial sample source.

BACKGROUND: Antimicrobial resistance is a major healthcare burden, aggravated when it extends to multiple drugs. While cross-resistance is well-studied experimentally, it is not the case in clinical settings, and especially not while considering confounding. Here, we estimated patterns of cross-resistance from clinical samples, while controlling for multiple clinical confounders and stratifying by sample sources. METHODS: We employed additive Bayesian network (ABN) modelling to examine antibiotic cross- resistance in five major bacterial species, obtained from different sources (urine, wound, blood, and sputum) in a clinical setting, collected in a large hospital in Israel over a 4-year period. Overall, the number of samples available were 3525 for E coli, 1125 for K pneumoniae, 1828 for P aeruginosa, 701 for P mirabilis, and 835 for S aureus. RESULTS: Patterns of cross-resistance differ across sample sources. All identified links between resistance to different antibiotics are positive. However, in 15 of 18 instances, the magnitudes of the links are significantly different between sources. For example, E coli exhibits adjusted odds ratios of gentamicin-ofloxacin cross-resistance ranging from 3.0 (95%CI [2.3,4.0]) in urine samples to 11.0 (95%CI [5.2,26.1]) in blood samples. Furthermore, we found that for P mirabilis, the magnitude of cross-resistance among linked antibiotics is higher in urine than in wound samples, whereas the opposite is true for K pneumoniae and P aeruginosa. CONCLUSIONS: Our results highlight the importance of considering sample sources when assessing likelihood of antibiotic cross-resistance. The information and methods described in our study can refine future estimation of cross-resistance patterns and facilitate determination of antibiotic treatment regimens.

Antibiotics are drugs that kill some bacteria. Antibiotic resistant bacteria are bacteria that continue to grow despite the presence of an antibiotic drug. These bacteria are a major problem in healthcare, particularly if the bacteria are resistant to multiple drugs. Here, we study bacteria that are resistant to several antibiotics that are present in patients in hospital. We find that patterns of cross-resistance differ between the location bacteria were sampled from, such as blood or urine. Our results highlight the importance of considering sample sources when assessing the likelihood that bacteria is resistant to multiple antibiotics. The information and methods described in our study should enable further analysis and prediction of the presence of cross-resistant bacteria, enabling appropriate antibiotic treatments to be used.