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Background & aimsMore data are needed regarding the long-term impact of the histological progression of non-alcoholic fatty liver disease (NAFLD) on long-term outcomes, including end-stage liver disease (ESLD) and mortality.MethodsWe included Swedish adults with biopsy-confirmed non-cirrhotic NAFLD and ≥2 liver biopsies >6 months apart (1969-2017; n = 718). NAFLD was categorized at initial biopsy as simple steatosis, non-fibrotic steatohepatitis (NASH), or non-cirrhotic fibrosis. NAFLD progression was defined by histological changes between biopsies (i.e. incident NASH, incident fibrosis, fibrosis progression, cirrhosis). Using Cox regression, we estimated multivariable adjusted hazard ratios (aHRs) and 95% CIs for incident ESLD (i.e. hospitalization for decompensated cirrhosis, hepatocellular carcinoma or liver transplantation) and mortality, according to NAFLD progression vs. stable/regressed disease.ResultsAt initial biopsy, 497 patients (69.2%) had simple steatosis, 90 (12.5%) had non-fibrotic NASH, and 131 (18.2%) had non-cirrhotic fibrosis. Over a median of 3.4 years between biopsies, 30.4% (218/718) experienced NAFLD progression, including 12.5% (62/497) with incident non-fibrotic NASH, 24.0% (141/587) with incident fibrosis, and 5.6% (40/718) with cirrhosis. Compared to stable/regressed disease, NAFLD progression was associated with significantly higher rates of developing incident ESLD (23.8 vs. 11.4/1,000 person-years [PY]; difference = 12.4/1,000 PY; aHR 1.65, 95% CI 1.17-2.32). While the highest ESLD incidence occurred with progression to cirrhosis (difference vs. stable/regressed disease = 56.3/1,000 PY), significant excess risk was also found with earlier transitions, including from simple steatosis to incident fibrosis (difference vs. stable/regressed disease = 18.9/1,000 PY). In contrast, all-cause mortality rates did not appear to differ when NAFLD progression was compared to stable/regressed disease (difference = 4.7/1,000 PY; aHR 0.99, 95% CI 0.78-1.24).ConclusionsIn a nationwide, real-world cohort of patients with paired NAFLD biopsies, histological disease progression contributed to significantly higher rates of developing incident ESLD, but did not appear to impact all-cause mortality.Impact and implicationsCurrently, data are scarce regarding the long-term impact of histological progression or regression of non-alcoholic fatty liver disease (NAFLD) on subsequent risk of adverse clinical outcomes, including the development of end-stage liver disease and mortality. This is particularly important because randomized-controlled trials of NAFLD therapeutics currently focus on short-term histological endpoints as presumed surrogates for those major clinical outcomes. Thus, the results from this study can help inform the optimal design of future NAFLD therapeutic trials, while also providing the necessary evidence base for public health policies focused on preventing the development and progression of NAFLD.

INTRODUCTION: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) vs. blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. MATERIALS AND METHODS: We assessed 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020. We determined recurrence rates and time to recurrence prior to BLC (ie, after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine association between BLC and recurrence, progression, and overall survival; and further, whether these outcomes differed by race. RESULTS: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. Median time to first recurrence following BLC was longer vs. WLC alone (40 [33-NE] vs. 26 [17-39] months). Recurrence risk was significantly lower following BLC (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.54-0.90). There was no significant difference in recurrence (HR 0.69; 95% CI, 0.39-1.20), progression (HR 1.13; 95% CI, 0.32-3.96), and overall survival (HR 0.74; 95% CI, 0.31-1.77) following BLC by Black vs. White race. CONCLUSION: In this study from an equal access setting in the VA, we observed significantly decreased recurrence risk and prolonged time interval to recurrence following BLC vs. WLC alone. There was no difference in bladder cancer outcomes by race.

Purpose: To compare the load and wellness of second-team academy football players during a first-team preseason with those of first-team players and those of their previous second-team preseason. Methods: Athletic Club's first- (n = 10) and second-team (n = 9) players were prospectively followed during the 2019–20 first- and second-team and 2020–21 first-team preseasons. Weekly external and internal loads and average wellness z-scores (fatigue, sleep quality, muscle soreness, stress, and mood) were compared between preseasons and teams. Results: While training together during the 2020–21 preseason, second-team players performed more decelerations <−3 m/s2 per week than first-team players (moderate effect size). For first-team players, there were only small differences between preseasons in external load, but session rating of perceived exertion was higher (moderate) and stress (moderate) and mood (large) z-scores were worse in 2020–21. For second-team players, more total distance (large), accelerations >3 m/s2 (large), and decelerations <−3 m/s2 (very large) were performed; total loading (moderate) and session rating of perceived exertion (moderate) were higher; and fatigue (very large) and stress (moderate) z-scores were worse during the 2020–21 first-team preseason compared to their previous second-team preseason. Conclusions: Players transitioning from the second team faced higher external and internal loads, fatigue, and stress during the first-team preseason compared to the previous second-team preseason. Player development and monitoring plans appear necessary to manage the transition from the academy to the first team. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EVs) are mediators between cancer cells and other types of cells, such as tumor-associated macrophages (TAMs), in the tumor microenvironment. EVs can remodel the tumor microenvironment and regulate tumor progression. However, the underlying molecular mechanism of these interactions remains unclear. Methods: First, we explored the effect of TAMs on the survival prognosis of patients with ovarian cancer. Next, we isolated EVs derived from ovarian cancer cells (OV-EVs) through ultracentrifugation and analyzed the capacity of OV-EVs to regulate macrophage polarization in ovarian tumors and in whole peripheral blood. Moreover, we explored the roles of OV-EVs-induced macrophages in tumor progression through in vitro and in vivo assays. Results: OV-EVs were encapsulated by macrophages and induced the polarization of macrophages toward the M2 phenotype. Moreover, OV-EVs-induced M2 macrophages promoted angiogenesis and cancer progression both in vitro and in vivo. In addition, OV-EVs-induced macrophages increased the expression level of VEGF and increased the expression level of VEGFR in tumors, which resulted in angiogenesis in ovarian cancer. Conclusions: The present study demonstrated that OV-EVs induce M2 polarization in macrophages and promote the progression of ovarian cancer. This study provides novel insight into the mechanism of ovarian cancer progression. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion To investigate the refractive error profile and progression in infants with different stages of ROP, without ROP, and those who received laser treatment for ROP.This retrospective study included the data from 838 infants (baseline mean age 3.7 ± 5.4 months) who had premature birth. Among these, 433 infants had one of the stages of ROP and 405 had no ROP. Infants with ROP were sub‐divided into stage 1 (n = 76), stage 2 (n = 142), and stage 3 (n = 136) and aggressive posterior ROP, (APROP, n = 79). They were further categorized into those who received treatment (n = 213) and with no treatment for ROP (n = 220). Data from a subset of 117 infants was used to assess the 1‐year change in the refractive error. Myopia was defined as spherical equivalent refraction (SER) <−0.50 diopters (D). Eyes with retinal detachment were excluded.Higher percentage of myopia was found in infants with ROP (39.7%) than no‐ROP (19.8%), and it increased with severity of ROP: stage 1: 19.7%, stage 2: 33.8%, stage 3: 45.6%, and 59.5% in APROP. Percentage of myopia doubled in those who underwent treatment for ROP (54.5%) compared to no‐treatment group (25.5%). Mean (± SEM) change in SER after 1 year was significantly greater in infants with APROP −4.55 ± 1.38 D and stage 3 ROP −2.28 ± 0.57 D compared to other stages and no‐ROP.Myopia was found to be more prevalent in preterm infants in general, and more in the presence of ROP. Preterm infants without or with any form of ROP, particularly those with severe form of ROP and those who received treatment require meticulous periodic refractive error assessment. [ABSTRACT FROM AUTHOR]

Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy‐Richardson's syndrome (PSP‐RS) patients with one‐year‐follow‐up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age‐matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas‐based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas‐based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The present study assessed the impact of glycyrrhizin on the mechanisms of progression and metastasis in cervical cancer cells. To this end, cell proliferation, migration, and invasion and protein/mRNA expression levels of protein kinase B, glycogen synthase kinase-3 β and β-catenin were measured in three groups of cells: normal cervical epithelial cell line End1/E6E7 (Group A), human cervical squamous cell carcinoma cell line C33a (group B), and human cervical squamous cell carcinoma cell line C33a treated with 50μmol/L glycyrrhizin (Group C). Results showed that glycyrrhizin treatment decreased the proliferation, migration, and invasion of C33a cells and increased apoptosis compared to the cervical cancer control cells. Expression levels of proteins associated with apoptosis such as FS-7-associated surface antigen, Bcl-2-associated X protein and Fas ligand were higher, while protein kinase B pathway activity was attenuated in the glycyrrhizin-treated group compared to the cervical cancer control group. These results suggest that glycyrrhizin may impair cervical cancer cell viability and impede their progression and metastasis by modulating the protein kinase B/glycogen synthase kinase-3β/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. Methods: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. Results: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. Discussion: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA–protein–mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance, compensatory hyperinsulinemia, and the development of hyperglycemia promote diabetic cardiomyopathy, a subtype of heart disease that develops apart from other cardiac risk factors like hypertension and coronary artery disease (CAD). The prevalence of heart failure symptoms was 19% in people with type 2 diabetes, and the chance of developing heart failure was two to eight times higher in those people. We intended to outline an overview of the Progression of Diabetic cardiomyopathy among Type 2 Diabetic Patients. Conclusions: Diabetes is one of the rare but rapidly increasing causes of cardiomyopathy globally. The condition is a common consequence of diabetes that is responsible for a great deal of death and disability. We provide a synopsis of the several potential pathogenic mechanisms that are now being studied that could lead to diabetes-related cardiomyopathy, including fibrosis, cell signaling disturbance, and left ventricular (LV) hypertrophy. Heart failure develops from these alterations. [ABSTRACT FROM AUTHOR]

Background Cognitive decline is among the most common non-motor symptoms in Parkinson's disease (PD), while its physiological mechanisms remain poorly understood. Genetic factors constituted a fundamental determinant in the heterogeneity of cognitive decline among PD patients. However, the underlying genetic background was still less studied. Methods To explore the genetic determinants contributing to cognitive decline in PD, we performed genome-wide survival analysis using a Cox proportional hazards model in a longitudinal cohort of 450 Chinese patients with PD, and further explored the functional effect of the target variant. Additionally, we built a clinical-genetic model by incorporating clinical characteristics and polygenic risk score (PRS) to predict cognitive decline in PD. Results The cohort was followed up for an average of 5.25 (SE  = 2.46) years, with 95 incidents of cognitive impairment. We identified significant association between locus rs75819919 (DPP6) and accelerated cognitive decline (p  = 8.63E-09, beta = 1.74, SE  = 0.30). Dual-luciferase reporter assay suggested this locus might be involved in the regulation of DPP6 expression. Using data set from the UK Biobank, we identified rs75819919 was associated with cognitive performance in the general population. Incorporation of PRS increased the model's predictability, achieving an average AUC of 75.6% through fivefold cross-validation in 1 000 iterations. Conclusions These findings improve the current understanding of the genetic etiology of cognitive impairment in PD, and provide a novel target DPP6 to explore therapeutic options. Our results also demonstrate the potential to develop clinical-genetic model to identify patients susceptible to cognitive impairment and thus provide personalized clinical guidance. [ABSTRACT FROM AUTHOR]

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established. Method: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis. Results: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16–1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001). Conclusion: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria. [ABSTRACT FROM AUTHOR]

Background We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case–control study. Methods Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan–Meier method. Results Thirty-two glioblastoma cases with positive COVID-19 testing were matched to 64 glioblastoma controls with negative testing; age, sex, and molecular profiles did not differ between groups. Progression events occurred in 27 cases (84%) and 46 controls (72%). Of these, 14 cases (52%) presented with multifocal disease or leptomeningeal disease at progression compared with 10 controls (22%; P  = .0082). Hyperprogression was identified in 13 cases (48%) but only 4 controls (9%; P  = .0001). Cases had disease progression at a median of 35 days following COVID-19 testing, compared with 164 days for controls (P  = .0001). Median survival from COVID-19 testing until death was 8.3 months for cases but 17 months for controls (P  = .0016). Median overall survival from glioblastoma diagnosis was 20.7 months for cases and 24.6 months for controls (P  = .672). Conclusions Patients with glioblastoma may have accelerated disease progression in the first 2 months after COVID-19 infection. Infected patients should be monitored vigilantly. Future investigations should explore tumor-immune microenvironment changes linking tumor progression and COVID-19. [ABSTRACT FROM AUTHOR]

Isthmic spondylolisthesis (IS) is defined as the anterior translation of one lumbar vertebra relative to the next caudal segment as a result of a unilateral or bilateral fracture of the pars interarticularis. These fractures are interchangeably known as "pars defects" or "spondylolysis." Many risk factors have been proposed to explain the progression of a spondylolytic defect to IS, however, none are validated. This systematic review provides an overview of various radiological and imaging parameters that can help predict the risk of progression of a spondylolytic defect into IS. Systematic review. Medline, Embase and Cochrane online database were searched. The various correlations between imaging features with observed spondylolisthesis prevalence or severity or spondylolysis rates of spondylolisthesis were evaluated to provide a list of imaging risk factors to predict IS. Significance of the correlations in the original article was recorded to enable comparison of the collected evidence of separate image features. All searches combined generated a total of 431 results of which 26 articles were included into this study. Of the 22 potential risk factors identified, 5 were found to be statistically insignificant, 8 were found to be significant and 9 had mixed results. The following features were found to be significant risk factors in at least on study: disc degeneration, transverse process width, pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, lumbar index, thoracic kyphosis, facet joint angle above the level of defect, facet joint degeneration, facet tropism, multifidus size, lateral erector spinae size, mesenteric fat thickness, subcutaneous fat thickness and soft tissue calcification. Our research suggests that only disc degeneration had moderately strong evidence with consistent significant associations with development of IS in patients with spondylolysis. Transverse process width, pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, lumbar index, thoracic kyphosis, facet joint angle above the level of defect, facet joint degeneration, facet tropism, multifidus size, lateral erector spinae size, mesenteric fat thickness, subcutaneous fat thickness and soft tissue calcification had some evidence. All other radiological factors had weak evidence. The results of this study can be used to improve early clinical decision making for patients with spondylolysis. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a malignant tumor originating from the epithelial cells of the renal tubules. The clear cell RCC subtype is closely linked to a poor prognosis due to its rapid progression. Circular RNA (circRNA) is a novel class of regulatory RNA molecules that play a role in the development of ccRCC, although their functions have not been fully elucidated. In this study, we identified a significant downregulation of circ-IP6K2 in ccRCC tissues based on data from the GSE100186 dataset. The decreased expression of circ-IP6K2 correlated with the progression of TNM stage and histological grade, and was also associated with decreased overall survival rates in ccRCC patients. Moreover, our findings revealed that circ-IP6K2 expression suppressed proliferation, migration, and invasion capabilities in vitro, and inhibited xenograft growth in vivo. Mechanistically, circ-IP6K2 acted as a sponge for miR-1292-5p in ccRCC cells, which in turn targeted the 3’UTR of CAMK2N1, leading to a decrease in its expression. CAMK2N1 was identified as a tumor suppressor that negatively regulated the β-catenin/c-Myc oncogenic signaling pathway. Additionally, we confirmed a positive correlation between the expression of circ-IP6K2 and CAMK2N1 in ccRCC. Circ-IP6K2 functions to impede the progression of ccRCC by modulating the miR-1292-5p/CAMK2N1 axis. These findings shed new light on the molecular mechanisms driving ccRCC progression and suggest potential therapeutic targets for the treatment of ccRCC. [ABSTRACT FROM AUTHOR]

Healthier lifestyle decreased the risk of mental disorders (MDs) such as depression and anxiety. However, research on the effects of a comprehensive healthy lifestyle on their progression is lacking. 385,704 individuals without baseline MDs from the UK Biobank cohort were included. A composite healthy lifestyle score was computed by assessing alcohol intake, smoking status, television viewing time, physical activity, sleep duration, fruit and vegetable intake, oily fish intake, red meat intake, and processed meat intake. Follow-up utilized hospital and death register records. Multistate model was used to examine the role of healthy lifestyle on the progression of specific MDs, while a piecewise Cox regression model was utilized to assess the influence of healthy lifestyle across various phases of disease progression. Higher lifestyle score reduced risks of transitions from baseline to anxiety and depression, as well as from anxiety and depression to comorbidity, with corresponding hazard ratios (HR) and 95 % confidence intervals (CI) of 0.94 (0.93, 0.95), 0.90 (0.89, 0.91), 0.94 (0.91, 0.98), and 0.95 (0.92, 0.98), respectively. Healthier lifestyle decreased the risk of transitioning from anxiety to comorbidity within 2 years post-diagnosis, with HR 0.93 (0.88, 0.98). Higher lifestyle scores at 2–4 years and 4–6 years post-depression onset were associated with reduced risk of comorbidity, with HR 0.93 (0.87, 0.99) and 0.92 (0.86, 0.99), respectively. The generalizability to other ethnic groups is limited. This study observed a protective role of holistic healthy lifestyle in the trajectory of MDs and contributed to identifying critical progression windows. • Evidence is scarce on association between a holistic healthy lifestyle and depression and anxiety comorbidity. • Trajectory and time courses of mental disorders need consideration. • Healthy lifestyle adherence inversely linked to mental disorder progression and prognosis. • Each lifestyle score increase reduces depression to comorbid anxiety by 6% and anxiety to comorbid depression by 5%. • Important progression windows were detected in the protective role of a holistic healthy lifestyle. [ABSTRACT FROM AUTHOR]

To investigate the progression of deep infiltrating endometriosis using transvaginal ultrasound surveillance of patients undergoing conservative management. Retrospective single cohort. Australian tertiary university hospital One hundred twenty two women with endometriosis proven on transvaginal ultrasound who had not undergone surgical management. The progression of endometriosis lesions demonstrated on transvaginal ultrasound in women receiving conservative management over the course of 24 months. A total of 122 patients fulfilled the inclusion criteria. All women had 2 ultrasounds that were performed at least 6 months apart. The median follow-up time was 490.5 days (255.4–725.6). At second scan, 22% (95% CI: 15–30%) of cohort experienced an increase in the number of endometriosis nodules compared to first scan, with 51% (95% CI: 42–60%) remaining static while 27% (95% CI: 19–35%) experienced a decrease. While there was no statistically significant difference in the volumes of uterosacral ligament, retro cervical, and bowel endometriosis, endometrioma volumes were significantly lower at second scan (Median = 3.24 mL, IQR = 0.6–16.87) as compared to the first scan (Median = 7.41 mL, IQR = 2.04–28.95), p <.001. Individuals with deep infiltrating endometriosis are unlikely to see significant disease progression over time. Both surgical and nonsurgical interventions are effective in managing endometriosis in terms of endometriotic nodule size and number, as measured by ultrasound. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Delivery by Caesarean section continues to rise globally and has been associated with the risk of developing type 1 diabetes and the rate of progression from pre-symptomatic stage 1 or 2 type 1 diabetes to symptomatic stage 3 disease. The aim of this study was to examine the association between Caesarean delivery and progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. Methods: Caesarean section was examined in 8135 children from the TEDDY study who had an increased genetic risk for type 1 diabetes and were followed from birth for the development of islet autoantibodies and type 1 diabetes. Results: The likelihood of delivery by Caesarean section was higher in children born to mothers with type 1 diabetes (adjusted OR 4.61, 95% CI 3.60, 5.90, p<0.0001), in non-singleton births (adjusted OR 4.35, 95% CI 3.21, 5.88, p<0.0001), in premature births (adjusted OR 1.91, 95% CI 1.53, 2.39, p<0.0001), in children born in the USA (adjusted OR 2.71, 95% CI 2.43, 3.02, p<0.0001) and in children born to older mothers (age group >28–33 years: adjusted OR 1.19, 95% CI 1.04, 1.35, p=0.01; age group >33 years: adjusted OR 1.80, 95% CI 1.58, 2.06, p<0.0001). Caesarean section was not associated with an increased risk of developing pre-symptomatic early-stage type 1 diabetes (risk by age 10 years 5.7% [95% CI 4.6%, 6.7%] for Caesarean delivery vs 6.6% [95% CI 6.0%, 7.3%] for vaginal delivery, p=0.07). Delivery by Caesarean section was associated with a modestly increased rate of progression to stage 3 type 1 diabetes in children who had developed multiple islet autoantibody-positive pre-symptomatic early-stage type 1 diabetes (adjusted HR 1.36, 95% CI 1.03, 1.79, p=0.02). No interaction was observed between Caesarean section and non-HLA SNPs conferring susceptibility for type 1 diabetes. Conclusions/interpretation: Caesarean section increased the rate of progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. Data availability: Data from the TEDDY study (https://doi.org/10.58020/y3jk-x087) reported here will be made available for request at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research (R4R) (https://repository.niddk.nih.gov/). [ABSTRACT FROM AUTHOR]

Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST. [ABSTRACT FROM AUTHOR]

Aims: Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device‐based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well‐defined cohorts for innovative preclinical and clinical trials. Methods and results: TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all‐cause mortality, to cardiovascular mortality, to heart failure mortality, to all‐cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. Conclusions: TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure. [ABSTRACT FROM AUTHOR]

Objectives: Lung adenocarcinoma (LUAD) is a malignant tumor originating from the bronchial mucosa or glands of the lung, with the fastest increasing morbidity and mortality. Therefore, the prognosis of lung cancer remains poor. Glycerol-3-phosphate dehydrogenase 2 (GPD2) is a widely existing protein pattern sequence in biology and is closely related to tumor progression. The therapy values of GPD2 inhibitor in LUAD were unclear. Therefore, we aimed to analyze the therapy values of GPD2 inhibitor in LUAD. Materials and methods: The Cancer Genome Atlas (TCGA)-LUAD database was used to analyze the expression levels of GPD2 in LUAD tissues. The relationship between GPD2 expression and LUAD patient survival was analyzed by Kaplan-Meier method. Moreover, KM04416 as a target inhibitor of GPD2 was used to further investigate the therapy value of GPD2 inhibitor in LUAD cells lines (A549 cell and H1299 cell). The TISIDB website was used to investigate the associations between GPD2 expression and immune cell infiltration in LUAD. Results: The results showed that GPD2 is overexpressed in LUAD tissues and significantly associated with poor survival. KM04416 can suppress the progression of LUAD cells by targeting GPD2. Low expression of GPD2 is related to high infiltration of immune cells. Conclusions: In summary, our present study found that targeting inhibition of GPD2 by KM04416 can suppress LUAD progression via adjusting immune cell infiltration. [ABSTRACT FROM AUTHOR]

Macular Telangiectasia Type 2 (MacTel) is a chronic, progressive disease of the central retina characterized by vascular and neurodegenerative changes. As there is currently no treatment for non-neovascular MacTel, there is a dearth for biomarkers identifying eyes with an increased risk for disease progression for patient counseling and clinical trial recruitment. Eyes were classified to be stable or progressive, defined by the fundus photography-based grading system by Gass and Blodi. First, structural differences between these two groups were assessed, employing optical coherence tomography (OCT) and OCT-angiography. Univariate regression analyses revealed evidence towards a lower superficial retinal layer (SRL) vessel density (VD), skeleton density (SD) and deep retinal layer (DRL) SD in progressing compared to stable eyes (p = 0.05, p = 0.05, p = 0.07). Second, a multivariable predictive model was employed to examine the predictive value of structural and functional parameters for disease progression. Baseline best corrected visual acuity (BCVA) and SRL SD are prognostic for disease progression (p < 0.001, p = 0.05). The presence of ellipsoid zone (EZ) loss is prognostic for future central retinal thickness (p < 0.01). We propose SRL SD, BCVA, and EZ loss as prognostic biomarkers and as possible outcome measures in future interventional studies in MacTel. [ABSTRACT FROM AUTHOR]

Prostate cancer remains a complex and challenging disease, necessitating innovative approaches for prognosis and therapeutic guidance. This study integrates machine learning techniques to develop a novel mitophagy-related long non-coding RNA (lncRNA) signature for predicting the progression of prostate cancer. Leveraging the TCGA-PRAD dataset, we identify a set of four key lncRNAs and formulate a riskscore, revealing its potential as a prognostic indicator. Subsequent analyses unravel the intricate connections between riskscore, immune cell infiltration, mutational landscapes, and treatment outcomes. Notably, the pan-cancer exploration of YEATS2-AS1 highlights its pervasive impact, demonstrating elevated expression across various malignancies. Furthermore, drug sensitivity predictions based on riskscore guide personalized chemotherapy strategies, with drugs like Carmustine and Entinostat showing distinct suitability for high and low-risk group patients. Regression analysis exposes significant correlations between the mitophagy-related lncRNAs, riskscore, and key mitophagy-related genes. Molecular docking analyses reveal promising interactions between Cyclophosphamide and proteins encoded by these genes, suggesting potential therapeutic avenues. This comprehensive study not only introduces a robust prognostic tool but also provides valuable insights into the molecular intricacies and potential therapeutic interventions in prostate cancer, paving the way for more personalized and effective clinical approaches. [ABSTRACT FROM AUTHOR]

The prognosis of patients with IgA nephropathy (IgAN) is variable but overall not good. Almost all patients with IgAN are at risk of developing end-stage renal disease within their expected lifetime. The models presently available for prediction of the risk of progression of IgAN, including the International IgA Nephropathy Prediction Tool, consist of traditional clinical, pathological, and therapeutic indicators. Finding biomarkers to improve the existing risk prediction models or replace pathological indicators is important for clinical practice. Many studies have attempted to identify biomarkers for prediction of progression of IgAN, such as galactose-deficient IgA1, complement, a spectrum of protein biomarkers, non-coding RNA, and shedding cells. This article reviews the biomarkers of progression of IgAN identified in recent years, with a focus on those with clinical value, in particular the combination of multiple biomarkers into a biomarker spectrum. Future research should focus on establishing a model based primarily on biomarkers that can predict progression of IgAN and testing it in various patient cohorts. [ABSTRACT FROM AUTHOR]

Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension complications. Its impact on hepatocellular carcinoma (HCC) remains unclear. We evaluated 42,843 liver transplant candidates with HCC from the Scientific Registry of Transplant Recipients (2002-2022). 4,484 patients with and without TIPS were propensity score-matched 1:3. Analysing wait-list changes in total tumor volume, HCC count, and alpha-fetoprotein levels, and assessing survival from listing and transplantation; TIPS correlated with a decreased nodule count (-0.24 vs. 0.04, p = 0.028) over a median wait period of 284 days (IQR 195-493) and better overall survival from listing (95.6%vs. 91.5% at 1 year, p < 0.0001). It was not associated with changes in tumor volume (0.28 vs. 0.11 cm³/month, p = 0.58) and AFP (14.37 vs. 20.67 ng/mL, p = 0.42). Post-transplant survival rates (91.8% vs. 91.7% at 1 year, p = 0.25) and HCC recurrence (5.1% vs. 5.9% at 5 years, p = 0.14) were similar, with a median follow-up of 4.98 years (IQR 2.5-8.08). While TIPS was associated with a reduced nodule count and improved waitlist survival, it did not significantly impact HCC growth or aggressiveness. These findings suggest potential benefits of TIPS in HCC management, but further studies need to confirm TIPS safety. [ABSTRACT FROM AUTHOR]

AbstractThe boundary between myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) has been revised in the latest World Health Organization classification of myeloid malignancies. These changes were motivated by the description of a subgroup of MDS patients identified as oligomonocytic chronic myelomonocytic leukemia (OM-CMML) at risk of evolving into overt CMML. Various studies will be reviewed describing the clinical and biological features of MDS patients evolving to CMML. The efforts to discover biomarkers enabling the identification of these patients at the time of MDS diagnosis will be discussed. Finally, the molecular landscape of these patients will be presented with a specific focus on the biallelic inactivation of TET2 in light of its functional impact on hematopoietic stem cells, granule-monocytic differentiation, and its tight interplay with inflammation. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, influenced by aberrant circRNA expression. Investigating circRNA-miRNA-mRNA interactions can unveil underlying mechanisms of HCC and identify potential therapeutic targets. Methods: In this study, we conducted differential analyses of mRNAs, miRNAs, and circRNAs, and established their relationships using various databases such as miRanda, miRDB, and miTarBase. Additionally, functional enrichment and immune infiltration analyses were performed to evaluate the roles of key genes. We also conducted qPCR assays and western blotting (WB) to examine the expression levels of circRNA, CCL25, and MAP2K1 in both HCC cells and clinical samples. Furthermore, we utilized overexpression and knockdown techniques for circ_0000069 and conducted wound healing, transwell invasion assays, and a tumorigenesis experiment to assess the migratory and invasive abilities of HCC cells. Results: Our findings revealed significant differential expression of 612 upregulated genes and 1173 downregulated genes in HCC samples compared to normal liver tissue. Additionally, 429 upregulated circRNAs and 453 downregulated circRNAs were identified. Significantly, circ_0000069 exhibited upregulation in HCC tissues and cell lines. The overexpression of circ_0000069 notably increased the invasion and migration capacity of Huh7 cells, whereas the downregulation of circ_0000069 reduced this capability in HepG2 cells. Furthermore, this effect was counteracted by CCL25 silencing or overexpression, separately. Animal studies further confirmed that the overexpression of hsa_circ_0000069 facilitated tumor growth in xenografted nude mice, while the inhibition of CCL25 attenuated this effect. Conclusion: Circ_0000069 appears to promote HCC progression by regulating CCL25, suggesting that both circ_0000069 and CCL25 can serve as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions We recently reported an increased risk of Parkinson's disease (PD) in service members who resided at Marine Base Camp Lejeune, North Carolina, when water supplies were contaminated with trichloroethylene and other volatile organic compounds (VOCs). Prior studies suggest that environmental exposures may affect PD phenotype or progression, but this has not been reported for VOCs.The objective of this study was to test whether PD progression is faster in individuals exposed to VOCs in water at Camp Lejeune.A cohort of 172,128 marines residing at Camp Lejeune between 1975 and 1985 was previously assembled. We identified individuals with PD in Veterans Health Administration and Medicare databases between 2000 and 2021. Using estimates derived by the US Agency for Toxic Substances and Disease Registry, we classified individuals as exposed or unexposed to VOCs in residential water. We used Kaplan–Meier and Cox regression models to test differences between exposed and unexposed groups in the time from PD diagnosis until psychosis, fracture, fall, or death.Among 270 persons with PD, 177 (65.6%) were exposed to VOCs in residential water. Median cumulative exposure was 4970 μg/L‐months, >50‐fold the permissible level. Time until psychosis, fracture, and fall were all shorter in the exposed group, with adjusted hazard ratios (HRs) exceeding 2: psychosis HR, 2.19 (95% confidence interval [CI]: 0.99–4.83); fracture HR, 2.44 (95% CI: 0.91–6.55); and fall HR, 2.64 (95% CI: 0.97–7.21). A significant dose response was observed for time to fall (P trend, 0.032). No differences were observed for time until death.PD progression may be faster in persons exposed to trichloroethylene and other VOCs in water decades earlier. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) affects roughly 1 in 7500 individuals. While at the population level there is a general pattern of affected muscles, there is substantial heterogeneity in muscle expression across- and within-patients. There can also be substantial variation in the pattern of fat and water signal intensity within a single muscle. While quantifying individual muscles across their full length using magnetic resonance imaging (MRI) represents the optimal approach to follow disease progression and evaluate therapeutic response, the ability to automate this process has been limited. The goal of this work was to develop and optimize an artificial intelligence-based image segmentation approach to comprehensively measure muscle volume, fat fraction, fat fraction distribution, and elevated short-tau inversion recovery signal in the musculature of patients with FSHD. Intra-rater, inter-rater, and scan-rescan analyses demonstrated that the developed methods are robust and precise. Representative cases and derived metrics of volume, cross-sectional area, and 3D pixel-maps demonstrate unique intramuscular patterns of disease. Future work focuses on leveraging these AI methods to include upper body output and aggregating individual muscle data across studies to determine best-fit models for characterizing progression and monitoring therapeutic modulation of MRI biomarkers. [ABSTRACT FROM AUTHOR]

Background: In early‐stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not well understood. Objectives: The objective is to determine whether iRWA was a mild form of RBD and progressed similarly over time. Methods: Participants with early PD (<4 years from medical diagnosis) were included from 2014 to 2021 in a longitudinal study. They underwent interviews and examinations in the motor, cognitive, autonomous, psychiatric, sensory, and sleep domains every year for 4 years along with a video polysomnography and magnetic resonance imaging examination of the locus coeruleus/subcoeruleus complex (LC/LsC) at baseline. The clinical characteristics were compared between groups with normal REM sleep, with iRWA and with RBD, at baseline and for 4 years. Results: Among 159 PD participants, 25% had RBD, 25% had iRWA, and 50% had normal REM sleep. At baseline, the non‐motor symptoms were less prevalent and the LC/LsC signal intensity was more intense in participants with iRWA than with RBD. Over 4 years, participants with normal REM sleep and with iRWA had a similar cognitive and motor trajectory, whereas participants with RBD had greater cognitive and motor decline. Conclusions: We demonstrated that iRWA is frequent in early PD, but is not a milder form of RBD. Both groups have distinct baseline characteristics and clinical trajectories. They should be distinguished in clinical routine and research protocols. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Lung adenocarcinoma (LUAD) is the most common malignant tumor in respiratory system. Methyltransferase‐like 1 (METTL1) is a driver of m7G modification in mRNA. This study aimed to demonstrate the role of METTL1 in the proliferation, invasion and Gefitinib‐resistance of LUAD. Methods: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells. Results: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G‐dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up‐regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD. [ABSTRACT FROM AUTHOR]

Circular RNAs are a class of noncoding RNAs with covalently linked 5′ and 3′ ends that arise from backsplicing events. The absence of a 5′ cap and a 3′ poly(A) tail makes circular RNAs relatively more stable than their linear counterparts. They are evolutionary conserved and tissue‐specific, and some show disease‐specific expression patterns. Although their biological functions remain largely unknown, circular RNAs have been shown to play regulatory roles by acting as microRNA sponges, regulators of RNA‐binding proteins, alternative splicing, and parental gene expression, and they could even encode proteins. Over the past few decades, circular RNAs have attracted wide attention in oncology owing to their implications in various tumors. Many circular RNAs have been characterized as key players in gastrointestinal cancers and influence cancer growth, progression, metastasis, and therapeutic resistance. Accumulating evidence reveals that their unique characteristics, coupled with their critical roles in tumorigenesis, make circular RNAs promising non‐invasive clinical biomarkers for gastrointestinal cancers. In the present review, we summarized the biological roles of the emerging circular RNAs and their potential as biomarkers and therapeutic targets, which may help better understand their clinical significance in the management of gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Background: Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. Methods: We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. Results: At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = −24/−17, 95% CI range = −31.60 to −10.40), B lymphocyte (coeff. range = −3.77/−2.54, 95% CI range = −6.02 to −0.35), memory regulatory B cells (coeff. range = −0.78/−0.57, 95% CI range = −1.24 to −0.17) and CD4/CD8 ratio (coeff. range = −4.44/−0.67, 95% CI range = −1.61 to −0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = −0.32/−0.24, 95% CI range = −0.59 to −0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = −4.23/−2.32, 95% CI range = −7.53 to −0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = −0.32/−0.24, 95% CI range = −0.59 to −0.03) vs. patients experiencing progression. Conclusions: Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study. [ABSTRACT FROM AUTHOR]

Objective: To clarify the impact of specific risk/protective factors on the disease progression and survival in a large population of Chinese sporadic ALS (sALS) patients. Methods: We investigated a cohort of 937 sALS patients prospectively. Uni‐ and multivariate regression analysis were performed to analyze the influence of demographic factors, comorbidities and medication on the progression and survival of ALS. Results: Our results showed younger age of onset (p < 0.05), long diagnostic delay (p < 0.001) and intake of riluzole (p < 0.001) were significantly related to low progression rate and long survival time. History of smoking (p < 0.05) and bulbar onset (p < 0.001) were risk factors for rapid progression and poor prognosis. Baseline ALSFRS‐R score (p < 0.001) and total MRC score (p < 0.05) were positively related to mean survival time of included patients. Neither comorbidities nor intake of antihypertensive drugs, antidiabetics, and statins as dependent variables showed considerable influence on ALS progression or survival. Conclusion: Our study revealed early onset and long diagnostic delay were indicators of slow progression and long survival. Smoking and bulbar onset were risk factors for shorter survival times and abstaining from smoking was beneficial to patients with ALS in improving median survival time. Long‐term intake of riluzole should be recommended for affordable patients. [ABSTRACT FROM AUTHOR]

Sarcomas, a group of neoplasms comprising both tissue and bone soft tissue tumors, has an increasing prevalence in recent years. Prognosis significantly hinges on early detection, and if not detected early, may consequently metastasize. This review will be the first systematic review and meta-analysis characterizing the presentation and progression of brain metastases from bone and soft tissue cancers. The PubMed, Scopus, and Web of Science databases were queried to identify studies reporting the incidence of intracranial brain metastases from primary sarcoma to the present. Abstract and full-text screening of 1822 initial articles returned by preliminary search yielded 28 studies for inclusion and data extraction. Qualitative assessment of the studies was conducted in accordance with the Newcastle–Ottawa Scale criteria. Meta-analyses were applied to assess risk factors on outcomes. The average age within the cohort was 27.9 years with a male and female prevalence of 59.1% and 40.9%, respectively. The odds ratio for living status (dead/alive) was calculated for several risk factors - male/female [OR 1.14, 95% CI 0.62, 2.07], single/multiple metastases [OR 0.67, 95% CI 0.35, 1.28], lung metastases/not [OR 1.63, 95% CI 0.85, 3.13], surgery/no surgery [OR 0.49, 95% CI 0.20, 1.21]. The standardized mean differences for duration from diagnoses to metastases were likewise analyzed - male/female [SMD 0.13, 95% CI -0.15, 0.42], single/multiple metastases [SMD 0.11, 95% CI -0.20, 0.42], lung metastases/not [SMD -0.03, 95% CI -0.38, 0.32], surgery/no surgery [SMD 0.45, 95% CI -0.18, 1.09]. The standardized mean differences for duration from metastases to death were analyzed - lung metastases/not [SMD 0.43, 95% CI -0.08, 0.95]. Our study observed no statistically significant differences in mortality rate among several patient risk factors. Consequentially, there lacks a clear answer as to whether or not an association between mortality rates exists with these patient factors. As such, it is important to continue research in brain-metastasizing sarcomas despite their relative rarity. [ABSTRACT FROM AUTHOR]

This chapter explores employer perspectives on the extension of behavioural conditionality to working social security claimants ('in-work conditionality'). As policymakers across Europe and other developed nations have pursued increasingly interventionist approaches to activating the unemployed through conditional welfare policies, the UK has gone a significant and 'unprecedented' step further by requiring those in receipt of in-work benefits to demonstrate their efforts to increase their working hours and/or pay. As the actors ultimately in control over the jobs people can access and progress in, understanding employer perspectives on this new policy development is critical, which, however, has so far been overlooked by policymakers and researchers. We address this omission through presenting original analysis of 84 semi-structured interviews conducted with a diverse group of employers. We find that while the UK's Work First approach to activation has seemingly encountered little resistance from employers to date, this new Work First, Work More approach may be a step too far. We contribute theoretically by identifying a potential role for employers as latent path disruptors in policy development, and challenge the commonly-held assumption that employers are typically supportive of extensions of behavioural conditionality to social security claimants. [ABSTRACT FROM AUTHOR]

Pediatric optic pathway/hypothalamic gliomas (OPHG) pose challenges in treatment due to their location and proximity to vital structures. Surgical resection plays a key role in the management of OPHG especially when the tumor exhibits mass effect and causes symptoms. However, data regarding outcomes and complications of surgical resection for OPHG remains heterogenous. The authors performed a systematic review on pediatric OPHG in four databases: PubMed, EMBASE, Cochrane Library, and Google Scholar. We included studies that reported on the visual outcomes and complications of OPHG resection. A meta-analysis was performed and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 26 retrospective studies were included. Seven hundred ninety-seven pediatric patients with OPHG undergoing surgical resection were examined. A diagnosis of NF1 was confirmed in 9.7%. Gross total resection was achieved in 36.7%. Intraorbital optic pathway gliomas showed a significantly higher gross total resection rate compared to those located in the chiasmatic/hypothalamic region (75.8% vs. 9.6%). Postoperatively, visual acuity improved in 24.6%, remained unchanged in 68.2%, and worsened in 18.2%. Complications included hydrocephalus (35.4%), anterior pituitary dysfunction (19.6%), and transient diabetes insipidus (29%). Tumor progression post-resection occurred in 12.8%, through a mean follow-up of 53.5 months. Surgical resection remains an essential strategy for treating symptomatic and large pediatric OPHG and can result in favorable vision outcomes in most patients. Careful patient selection is critical. Patients should be monitored for hydrocephalus development postoperatively and followed up to assess for tumor progression and adjuvant treatment necessity. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the oncological impact of micrometric extent of invasion in patients with pT1 bladder cancer (BCa) who underwent en‐bloc resection for bladder tumour (ERBT). Methods and results: We retrospectively analysed the records and specimens of 106 pT1 high‐grade BCa patients who underwent ERBT. The extent of invasion, such as depth from basal membrane, number of invasive foci, maximum width of invasive focus, muscularis mucosae invasion and infiltration pattern (pattern A: solid sheet‐like, nodular or nested growth, pattern B: trabecular, small cluster or single‐cell pattern) were evaluated by a single genitourinary pathologist. The end‐points were recurrence‐free (RFS) and progression‐free survival (PFS). Within a median follow‐up of 23 months, overall, 36 patients experienced recurrence and 13 patients experienced disease progression. The 2‐year PFS differed significantly depending on depth from basal membrane (< 1.3 mm: 94.8% versus ≧ 1.3 mm: 65.2%, P = 0.005), maximum width of invasive focus (< 4 mm: 91.7% versus ≧ 4 mm: 62.3%, P < 0.001), muscularis mucosae (MM) invasion (above MM = 96.1% versus into or beyond MM = 64.8%, P = 0.002) and infiltration pattern (pattern A: 100% versus pattern B: 83.3%, P = 0.037). In a multivariable analysis, MM invasion [hazard ratio (HR) = 4.54, 95% confidence interval (CI) = 1.25–16.5] and maximum width of invasive focus ≧ 4 mm (HR = 4.79, 95% CI = 1.25–16.5) were independent prognostic factors of progression. Conclusions: En‐bloc resection facilitates the evaluation of pathologic variables that might be useful in predicting disease recurrence and progression. In particular, not only the MM invasion but also the maximum width of invasion focus, reflecting the invasive volume, appear to be reliable prognosticators for disease progression. [ABSTRACT FROM AUTHOR]

Normocalcemic hyperparathyroidism (NHPT) is variably defined, and information regarding complications and natural history are scarce. We aimed to describe the phenotype of NHPT in relation to hypercalcemic hyperparathyroidism (PHPT) and controls, to determine risk of progression, and to develop a predictive model for progression to PHPT. This is a retrospective chart review of 232 patients at a tertiary medical center, comparing 75 controls, 73 patients with NHPT, and 84 with PHPT. NHPT was intermediate in biochemical profile between controls and PHPT with respect to cCa, iPTH, intraindividual coefficient of variant of cCa, phosphorus, and 25(OH)D. NHPT patients had an increased adjusted risk of urolithiasis (OR 5.34, 95%CI, 2.41-12.71, P  < .001) and fragility fractures (OR 4.53, 95%CI, 1.63-14.84, P  = .006) versus controls, after adjustment for age, sex, and BMI. Fewer NHPT compared with PHPTH patients achieved cure with parathyroidectomy (P  = .001). NHPT more often had nonlocalizing imaging or polyglandular disease (P  = .005). Parathyroidectomy improved biochemical but not BMD parameters in NHPT. Over a median follow-up of 4.23 (IQR 1.76-5.31) years, NHPT patients managed expectantly experienced no change in iPTH, and progression to PHPT occurred in 9%. An XGBoost model combining 6 factors for progression (mean index 2 iPTH, mean index 2 cCa, 24-h urinary calcium, age, 25(OH)D, and presence of urolithiasis) had an area under the curve 1.00 (95%CI, 1.00-1.00, P  < .001) for predicting combined progression. NHPT is a mild variant of PHPT at intermediate risk of urolithiasis and fragility fractures. Cure was less often achieved with parathyroidectomy, which did not improve BMD parameters. Progression was infrequent with conservative management. Because only a minority progressed to PHPT, in addition to lower surgical success rates, we suggest conservative management for the majority of NHPT unless risk factors for progression are identified. [ABSTRACT FROM AUTHOR]

It is often presumed that when students complete a particular entry course at college, the acquisition of that qualification should grant access to the next, higher level of study. There is a dearth of academic research on the actual progression outcomes for so-called not in education, employment, and training (NEET) and disengaged youth, enrolled on an employability course. Purportedly, the employability qualifications should enable students to progress towards higher levels of study, but do they? Adopting a case study approach, research was conducted with seven tutors and 26 students enrolled on the 2013 and 2014 Level 1 Achieving Skills Course, an employability course delivered at The Site, a FE college in the East Region. The college’s database was also accessed to review success and progression outcomes. Highlighting discrepancy and controversy, key findings revealed that most participants were unable to progress onto higher level courses at The Site. Instead, they were recorded as either NEET or destination unknown. This paper reveals key factors impeding progression and the reification of NEET identities on this course. It calls for political debate and a sharper inspection into the quality of re-engagement provisions for so-called NEET and disengaged youth. [ABSTRACT FROM AUTHOR]