Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Cardiovascular-specific mortality and risk factors in colorectal Cancer patients: A cohort study based on registry data of over 500,000 individuals in the US.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and recent studies have found that CRC patients are at increased risk for cardiovascular disease (CVD). This study aimed to investigate competing causes of death and prognostic factors among a large cohort of CRC patients and to describe cardiovascular-specific mortality in relation to the US standard population. METHODS: This registry-based cohort study identified patients diagnosed with CRC between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Cumulative mortality functions, conditional standardized mortality ratios, and cause-specific hazard ratios were calculated. RESULTS: Of the 563,298 eligible CRC patients included in this study, 407,545 died during the follow-up period. CRC was the leading cause of death, accounting for 49.8% of all possible competing causes of death. CVD was the most common non-cancer cause of death, accounting for 17.8% of total mortality. This study found that CRC patients have a significantly increased risk of cardiovascular-specific mortality compared to the US standard population, with the risk increasing with age and extended survival time. CONCLUSION: This study highlights the need to develop multidisciplinary prevention and management strategies for CRC and CVD to improve CRC patients' survival and quality of life.

Imaging of Biliary Tree Abnormalities.

Pathologic conditions of the biliary system, although common, can be difficult to diagnose clinically. Challenges in biliary imaging include anatomic variants and the dynamic nature of the biliary tract, which can change with age and intervention, blurring the boundaries of normal and abnormal. Choledochal cysts can have numerous appearances and are important to diagnose given the risk of cholangiocarcinoma potentially requiring surgical resection. Choledocholithiasis, the most common cause of biliary dilatation, can be difficult to detect at US and CT, with MRI having the highest sensitivity. However, knowledge of the imaging pitfalls of MRI and MR cholangiopancreatography is crucial to avoid misinterpretation. Newer concepts in biliary tract malignancy include intraductal papillary biliary neoplasms that may develop into cholangiocarcinoma. New paradigms in the classification of cholangiocarcinoma correspond to the wide range of imaging appearances of the disease and have implications for prognosis. Accurately staging cholangiocarcinoma is imperative, given expanding curative options including transplant and more aggressive surgical options. Infections of the biliary tree include acute cholangitis or recurrent pyogenic cholangitis, characterized by obstruction, strictures, and central biliary dilatation. Inflammatory conditions include primary sclerosing cholangitis, which features strictures and fibrosis but can be difficult to differentiate from secondary causes of sclerosing cholangitis, including more recently described entities such as immunoglobulin G4-related sclerosing cholangitis and COVID-19 secondary sclerosing cholangitis. The authors describe a wide variety of benign and malignant biliary tract abnormalities, highlight differentiating features of the cholangitides, provide an approach to interpretation based on the pattern of imaging findings, and discuss pearls and pitfalls of imaging to facilitate accurate diagnosis. ©RSNA, 2024 Supplemental material is available for this article.

Fosfatriclaben: Effective dose determination and comparative efficacy assessment with closantel, triclabendazole+ivermectin, triclabendazole+albendazole in artificially infected cattle.

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.

Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies.

Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA.

The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. SUMMARY: Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1ß and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.

Validation of a Hybrid Exoskeleton for Upper Limb Rehabilitation. A Preliminary Study.

Recovery of therapeutic or functional ambulatory capacity in patients with rotator cuff injury is a primary goal of rehabilitation. Wearable powered exoskeletons allow patients to perform repetitive practice with large movements to maximize recovery, even immediately after the acute event. The aim of this paper is to describe the usability, acceptability and acceptance of a hybrid exoskeleton for upper-limb passive rehabilitation using the System Usability Scale (SUS) questionnaire. This equipment, called ExoFlex, is defined as a hybrid exoskeleton since it is made up of rigid and soft components. The exoskeleton mechanical description is presented along with its control system and the way motion is structured in rehabilitation sessions. Seven patients (six women and one man) have participated in the evaluation of this equipment, which are in the range of 50 to 79 years old. Preliminary evidence of the acceptance and usability by both patients and clinicians are very promising, obtaining an average score of 80.71 in the SUS test, as well as good results in a questionnaire that evaluates the clinicians' perceived usability of ExoFlex.

Influence of stroke rate on coordination and sprint performance in elite male and female swimmers.

This study investigated the effects of gender and the manipulation of the preferred stroke rate on swimming performance and arm coordination in elite front crawl swimmers. Nineteen swimmers performed a dual task, that is, imposed stroke rate and maximal speed. They swam nine 25-m trials at maximal speed twice: one trial at the preferential stroke rate, one trial at maximal stroke rate and seven trials at stroke rates between 41 and 59 cycles/min imposed by an Aquapacer. Stroke rate, arm stroke phases, and arm coordination were computed from an inertial measurement unit on each forearm and one on the sacrum. Time on the 25-m was recorded to assess swimming speed. Results indicated that the error between the imposed and performed stroke rates was lowest at the preferred stroke rate for women. An increase in stroke rate led to an increase in swimming speed and the index of coordination, but these changes could be influenced by the preferred stroke rate. Individual analysis revealed that some swimmers exhibited higher flexibility (larger range of stroke rate) around their preferred stroke rate. This stroke rate flexibility appeared more functional in swimmers who reached higher speeds when swimming at the maximal stroke rate than at the preferred stroke rate.

Reversible Nanogate System for Mesoporous Silica Nanoparticles Based on Diels-Alder Adducts.

The implementation of nanoparticles as nanomedicines requires sophisticated surface modifications to reduce the immune response and enhance recognition abilities. Mesoporous silica nanoparticles present extraordinary host-guest abilities and facile surface functionalization. These two factors make them ideal candidates for the development of novel drug-delivery systems, at the expense of increasing structural complexity. With this idea in mind, a system composed of triggerable and tunable silica nanoparticles was developed for application as drug-delivery nanocarriers. Diels-Alder cycloaddition adducts were chosen as thermal-responsive units that permitted the binding of gold nanocaps able to block the pores and allow the incorporation of targeting fragments. The capping efficiency was tested under different thermal conditions to give outstanding efficiencies within the physiological range and mild temperatures, as well as enhanced release under pulsing heating cycles, which showed the best release profiles.

Functional Role of Movement and Performance Variability: Adaptation of Front Crawl Swimmers to Competitive Swimming Constraints.

To study the variability in stroking parameters between and within laps and individuals during competitions, we compared and modeled the changes of speed, stroke rate, and stroke length in 32 top-level male and female swimmers over 4 laps (L1-L4) in 200-m freestyle events using video-derived 2-dimensional direct linear transformation. For the whole group, speed was greater in L1, with significant decreases across L2, L3, and L4 (1.80 ± 0.10 vs 1.73 ± 0.08; 1.69 ± 0.09; 1.66 ± 0.09  · s-1, P < .05). This variability was attributed to a decrease in stroke length (L2: 2.43 ± 0.19 vs L4: 2.20 ± 0.13 m, P < .05) and an increase in stroke rate (L2: 42.8 ± 2.6 vs L4: 45.4 ± 2.3 stroke · min-1, P < .05). The coefficient of variation and the biological coefficient of variation in speed were greater for male versus female (3.9 ± 0.7 vs 3.1 ± 0.7; 2.9 ± 1.0 vs 2.6 ± 0.7, P < .05) and higher in L1 versus L2 (3.9 ± 1.3 vs 3.1 ± 0.1; 2.9 ± 0.9 vs 2.3 ± 0.7, P < .05). Intra-lap speed values were best represented by a cubic (n = 38), then linear (n = 37) and quadratic model (n = 8). The cubic fit was more frequent for males (43.8%) than females (15.6%), suggesting greater capacity to generate higher acceleration after the turn. The various stroking parameters managements within lap suggest that each swimmer adapts his/her behavior to the race constraints.

Developmental SALL2 transcription factor: a new player in cancer.

SALL2, also known as Spalt-like transcription factor 2, is a member of the SALL family of transcription factors involved in development and conserved through evolution. Since its identification in 1996, findings indicate that SALL2 plays a role in neurogenesis, neuronal differentiation and eye development. Consistently, SALL2 deficiency associates with neural tube defects and coloboma, a congenital eye disease. Relevant to cancer, clinical studies indicate that SALL2 is deregulated in various cancers and is a specific biomarker for Synovial Sarcoma. However, the significance of SALL2 deregulation in this disease is controversial. Here, we present and discuss all available information about SALL2 since its discovery, including isoforms, regulation, targets and functions. We specifically discuss the role of SALL2 in the regulation of cell proliferation and survival within the context of the identified target genes, its interaction with viral oncogenes, and its association with the TP53 tumor suppressor and MYC oncogene. Special attention is given to p53-independent SALL2 regulation of pro-apoptotic genes BAX and PMAIP1, and the implication of these findings on the apoptotic response of cancer cells to therapy. Understanding SALL2 function and the molecular mechanisms governing its expression and activity is critical to comprehend why and how SALL2 could contribute to disease. This knowledge will open new perspectives for the development of molecular targeted approaches in disease.

α-Catenin phosphorylation promotes intercellular adhesion through a dual-kinase mechanism.

The cadherin-catenin adhesion complex is a key contributor to epithelial tissue stability and dynamic cell movements during development and tissue renewal. How this complex is regulated to accomplish these functions is not fully understood. We identified several phosphorylation sites in mammalian αE-catenin (also known as catenin α-1) and Drosophila α-Catenin within a flexible linker located between the middle (M)-region and the carboxy-terminal actin-binding domain. We show that this phospho-linker (P-linker) is the main phosphorylated region of α-catenin in cells and is sequentially modified at casein kinase 2 and 1 consensus sites. In Drosophila, the P-linker is required for normal α-catenin function during development and collective cell migration, although no obvious defects were found in cadherin-catenin complex assembly or adherens junction formation. In mammalian cells, non-phosphorylatable forms of α-catenin showed defects in intercellular adhesion using a mechanical dispersion assay. Epithelial sheets expressing phosphomimetic forms of α-catenin showed faster and more coordinated migrations after scratch wounding. These findings suggest that phosphorylation and dephosphorylation of the α-catenin P-linker are required for normal cadherin-catenin complex function in Drosophila and mammalian cells.

Rheb promotes cancer cell survival through p27Kip1-dependent activation of autophagy.

We previously found that the small GTPase Rheb regulates the cell-cycle inhibitor p27KIP1 (p27) in colon cancer cells by a mTORC1-independent mechanism. However, the biological function of the Rheb/p27 axis in cancer cells remains unknown. Here, we show that siRNA-mediated depletion of Rheb decreases survival of human colon cancer cells under serum deprivation. As autophagy can support cell survival, we analyzed the effect of Rheb on this process by detecting the modification of the autophagy marker protein LC3 by western blot and imunofluorescence. We found that Rheb promotes autophagy in several human cancer cell lines under serum deprivation. Accordingly, blocking autophagy inhibited the pro-survival effect of Rheb in colon cancer cells. We then analyzed whether p27 was involved in the biological effect of Rheb. Depletion of p27 inhibited colon cancer cell survival, and Rheb induction of autophagy. These results suggest that p27 has an essential role in the effect of Rheb in response to serum deprivation. In addition, we demonstrated that the role of p27 in autophagy stands on the N-terminal portion of the protein, where the CDK-inhibitory domain is located. Our results indicate that a Rheb/p27 axis accounts for the activation of autophagy that supports cancer cell survival. Our work therefore highlights a biological function of Rheb and prompts the need for future studies to address whether the mTORC1-independent Rheb/p27 axis could contribute to tumorigenesis and/or resistance to mTOR inhibitors.

Small bowel pyloric metaplasia is associated with lower rates of earlier recurrence of Crohn's disease after resection.

Recurrence within one or two years is common after Crohn's disease (CD) resection. In this study, we seek to identify histologic features in CD resections that may predict earlier (≤18 months) recurrence to potentially guide post-operative management. A single-institution, retrospective review was performed on patients with first-time CD bowel resection specimens (2002-2007). Patient demographics and CD course were also documented. Slides were reviewed for inflammatory distribution and composition, small bowel (SB) pyloric metaplasia (PM), and presence and characteristics of submucosal fibrosis and granulomas. In our cohort, 14 of 41 patients experienced earlier clinical or endoscopic recurrence after initial resection. In the 38 patients who underwent SB resection (3 were colon only), PM was less common in those with earlier recurrence (6/12 [50%]) compared to those with later (>18 months) or no known recurrence (22/26 [85%]) (P = 0.045). PM was present even in patients with <1 year of known CD. Additionally, therapy with anti-tumor necrosis factor (TNF) prior to surgery was more common in earlier recurrence patients (7/14 [50%]) than later or no recurrence patients (4/27 [15%]) (P = 0.026). There was no significant difference in age, sex, smoking status, duration of CD, post-operative CD medication, distribution or features of inflammation, granulomas, or fibrosis. Overall, our results indicate that SB PM and pre-surgical anti-TNF therapy are possible helpful clinicopathologic features to evaluate for recurrence risk.

Imaging of pancreatic serous cystadenoma and common imitators.

Pancreatic cystic neoplasms are lesions comprised of cystic components that show different biological behaviors, epidemiology, clinical manifestations, imaging features, and malignant potential and management. Benign cystic neoplasms include serous cystic neoplasms (SCAs). Other pancreatic cystic lesions have malignant potential, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. SCAs can be divided into microcystic (classic appearance), honeycomb, oligocystic/macrocystic, and solid patterns based on imaging appearance. They are usually solitary but may be multiple in von Hippel-Lindau disease, which may depict disseminated involvement. The variable appearances of SCAs can mimic other types of pancreatic cystic lesions, and cross-sectional imaging plays an important role in their differential diagnosis. Endoscopic ultrasonography has helped in improving diagnostic accuracy of pancreatic cystic lesions by guiding tissue sampling (biopsy) or cyst fluid analysis. Immunohistochemistry and newer techniques such as radiomics have shown improved performance for preoperatively discriminating SCAs and their mimickers.

Tailored Coatings for Enhanced Performance of Zinc-Magnesium Alloys in Absorbable Implants.

Absorbable metals exhibit potential for next-generation temporary medical implants, dissolving safely in the body during tissue healing and regeneration. Their commercial incorporation could substantially diminish the need for additional surgeries and complications that are tied to permanent devices. Despite extensive research on magnesium (Mg) and iron (Fe), achieving the optimal combination of mechanical properties, biocompatibility, and controlled degradation rate for absorbable implants remains a challenge. Zinc (Zn) and Zn-based alloys emerged as an attractive alternative for absorbable implants, due to favorable combination of in vivo biocompatibility and degradation behavior. Moreover, the development of suitable coatings can enhance their biological characteristics and tailor their degradation process. In this work, four different biodegradable coatings (based on zinc phosphate (ZnP), collagen (Col), and Ag-doped bioactive glass nanoparticles (AgBGNs)) were synthesized by chemical conversion, spin-coating, or a combination of both on Zn-3Mg substrates. This study assessed the impact of the coatings on in vitro degradation behavior, cytocompatibility, and antibacterial activity. The ZnP-coated samples demonstrated controlled weight loss and a decreased corrosion rate over time, maintaining a physiological pH. Extracts from the uncoated, ZnP-coated, and Col-AgBGN-coated samples showed higher cell viability with increasing concentration. Bacterial viability was significantly impaired in all coated samples, particularly in the Col-AgBGN coating. This study showcases the potential of a strategic material-coating combination to effectively tackle multiple challenges encountered in current medical implant technologies by modifying the properties of absorbable metals to tailor patient treatments.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Histologic Features of Liver Injury Associated With SARS-CoV-2 Messenger RNA Vaccines.

CONTEXT.­: Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported. OBJECTIVE.­: To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury. DESIGN.­: Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed. RESULTS.­: All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy except one patient who developed autoimmune hepatitis. CONCLUSIONS.­: Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition.

Single-cell RNA sequencing reveals the MIF/ACKR3 receptor-ligand interaction between neutrophils and nucleus pulposus cells in intervertebral disc degeneration.

OBJECTIVES: To unravel the heterogeneity and function of microenvironmental neutrophils during intervertebral disc degeneration (IDD). METHODS: Single-cell RNA sequencing (scRNA-seq) was utilized to dissect the cellular landscape of neutrophils in intervertebral disc (IVD) tissues and their crosstalk with nucleus pulposus cells (NPCs). The expression levels of macrophage migration inhibitory factor (MIF) and ACKR3 in IVD tissues were detected. The MIF/ACKR3 axis was identified and its effects on IDD were investigated in vitro and in vivo. RESULTS: We sequenced here 71520 single cells from 5 control and 9 degenerated IVD samples using scRNA-seq. We identified a unique cluster of neutrophils abundant in degenerated IVD tissues that highly expressed MIF and was functionally enriched in extracellular matrix organization (ECMO). Cell-to-cell communication analyses showed that this ECMO-neutrophil subpopulation was closely interacted with an effector NPCs subtype, which displayed high expression of ACKR3. Further analyses revealed that MIF was positively correlated with ACKR3 and functioned via directly binding to ACKR3 on effector NPCs. MIF inhibition attenuated degenerative changes of NPCs and extracellular matrix, which could be partially reversed by ACKR3 overexpression. Clinically, a significant correlation of high MIF/ACKR3 expression with advanced IDD grade was observed. Furthermore, we also found a positive association between MIF+ ECMO-neutrophil counts and ACKR3+ effector NPCs density as well as higher expression of the MIF/ACKR3 signaling in areas where these two cell types were neighbors. CONCLUSIONS: These data suggest that ECMO-neutrophil promotes IDD progression by their communication with NPCs via the MIF/ACKR3 axis, which may shed light on therapeutic strategies.