Treatment for appendicitis in cancer patients on chemotherapy: a retrospective cohort study.

Purpose: Whether to perform surgery or conservatively manage appendicitis in immunosuppressed patients is a concern for clinicians. This study aimed to compare the outcomes of these 2 treatment options for appendicitis in patients with cancer undergoing chemotherapy. Methods: This retrospective study included 206 patients with cancer who were diagnosed with acute appendicitis between August 2001 and December 2021. Among them, patients who received chemotherapy within 1 month were divided into surgical and conservative groups. We evaluated the outcomes, including treatment success within 1 year, 1-year recurrence, and the number of days from the diagnosis of appendicitis to chemotherapy restart, between the 2 groups. Results: Among the 206 patients with cancer who were diagnosed with acute appendicitis, 78 received chemotherapy within 1 month. The patients were divided into surgery (n = 63) and conservative (n = 15) groups. In the surgery group, the duration of antibiotic therapy (7.0 days vs. 16.0 days, P < 0.001) and length of hospital stay (8.0 days vs. 27.5 days, P = 0.002) were significantly shorter than conservative groups. The duration from the diagnosis of appendicitis to the restart of chemotherapy was shorter in the surgery group (20.8 ± 15.1 days vs. 35.2 ± 28.2 days, P = 0.028). The treatment success rate within 1 year was higher in the surgery group (100% vs. 33.3%, P < 0.001). Conclusion: Surgical treatment showed a significantly higher success rate than conservative treatment for appendicitis in patients less than 1 month after chemotherapy. Further prospective studies will be needed to clinically determine treatment options.

Extended MOF-74-Type Variant with an Azine Linkage: Efficient Direct Air Capture and One-Pot Synthesis.

Direct air capture (DAC) shows considerable promise for the effective removal of CO2; however, materials applicable to DAC are lacking. Among metal-organic framework (MOF) adsorbents, diamine-Mg2(dobpdc) (dobpdc4- = 4,4-dioxidobiphenyl-3,3'-dicarboxylate) effectively removes low-pressure CO2, but the synthesis of the organic ligand requires high temperature, high pressure, and a toxic solvent. Besides, it is necessary to isolate the ligand for utilization in the synthesis of the framework. In this study, we synthesized a new variant of extended MOF-74-type frameworks, M2(hob) (M = Mg2+, Co2+, Ni2+, and Zn2+; hob4- = 5,5'-(hydrazine-1,2-diylidenebis(methanylylidene))bis(2-oxidobenzoate)), constructed from an azine-bonded organic ligand obtained through a facile condensation reaction at room temperature. Functionalization of Mg2(hob) with N-methylethylenediamine, N-ethylethylenediamine, and N,N'-dimethylethylenediamine (mmen) enables strong interactions with low-pressure CO2, resulting in top-tier adsorption capacities of 2.60, 2.49, and 2.91 mmol g-1 at 400 ppm of CO2, respectively. Under humid conditions, the CO2 capacity was higher than under dry conditions due to the presence of water molecules that aid in the formation of bicarbonate species. A composite material combining mmen-Mg2(hob) and polyvinylidene fluoride, a hydrophobic polymer, retained its excellent adsorption performance even after 7 days of exposure to 40% relative humidity. In addition, the one-pot synthesis of Mg2(hob) from a mixture of the corresponding monomers is achieved without separate ligand synthesis steps; thus, this framework is suitable for facile large-scale production. This work underscores that the newly synthesized Mg2(hob) and its composites demonstrate significant potential for DAC applications.

A high reticulocyte count is a risk factor for the onset of metabolic dysfunction-associated steatotic liver disease: Cross-sectional and prospective studies of data of 310,091 individuals from the UK Biobank.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a considerable health risk. Nevertheless, its risk factors are not thoroughly comprehended, and the association between the reticulocyte count and MASLD remains uncertain. This study aimed to explore the relationship between reticulocyte count and MASLD. Methods: A total of 310,091 individuals from the UK Biobank were included in this cross-sectional study, and 7,316 individuals were included in this prospective study. The cross-sectional analysis categorized reticulocyte count into quartiles, considering the sample distribution. Logistic regression models examined the connection between reticulocyte count and MASLD. In the prospective analysis, Cox analysis was utilized to investigate the association. Results: Our study findings indicate a significant association between higher reticulocyte count and an elevated risk of MASLD in both the cross-sectional and prospective analyses. In the cross-sectional analysis, the adjusted odds ratios (ORs) of MASLD increased stepwise over reticulocyte count quartiles (quartile 2: OR 1.22, 95% CI 1.17-1.28, p < 0.001; quartile 3: OR 1.44; 95% CI 1.38-1.51, p < 0.001; quartile 4: OR 1.66, 95% CI 1.59-1.74, p < 0.001). The results of prospective analyses were similar. Conclusion: Increased reticulocyte count was independently associated with a higher risk of MASLD. This discovery offers new insights into the potential of reticulocytes as biomarkers for MASLD.

Tailored Postsynthetic Nitration of a Hypercrosslinked Polymer for Single-Step Ethylene Purification from a Ternary C2 Gas Mixture.

Purifying C2H4 from a ternary C2H2/C2H4/C2H6 mixture poses a substantial industrial challenge due to their close physical and chemical properties. In this study, we introduce an innovative design approach to regulate and optimize the nitration degree of a hypercrosslinked polymer to achieve targeted separation performance. We synthesized a porous organic polymer (HCP) using the solvent knitting method and carried out its postsynthetic nitration, resulting in HCP-NO2-1 and HCP-NO2-2 with different nitration degrees. Notably, the adsorption capacity shifted from C2H6 > C2H4 ≈ C2H2 for HCP to C2H2 > C2H6 > C2H4 for HCP-NO2-1 and to C2H2 > C2H4 ≈ C2H6 for HCP-NO2-2, demonstrating the controllable nature of the separation process via the polar nitro group insertion. Remarkably, HCP-NO2-1 exhibited a desirable, selective separation of C2H4 from the C2H6/C2H4/C2H2 mixture thanks to an exquisite combination of the acidic proton-polar nitro group and nonpolar C-H∙∙∙π interactions. Separation capability was further corroborated by computational simulations and breakthrough tests. This work marks a significant advancement as the first successful postsynthetic functionalization strategy for C2H4 purification from a ternary gas mixture among porous organic polymers.

Polygenic risk score of metabolic dysfunction-associated steatotic liver disease amplifies the health impact on severe liver disease and metabolism-related outcomes.

BACKGROUND: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. METHODS: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. RESULTS: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. CONCLUSIONS: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.

Accuracy of traditional open-tray impression, stereophotogrammetry, and intraoral scanning with prefabricated aids for implant-supported complete arch prostheses with different implant distributions: An in vitro study.

STATEMENT OF PROBLEM: Conventional impression techniques for complete arch implant-supported fixed dental prostheses (CIFDPs) are technique sensitive. Stereophotogrammetry (SPG) and intraoral scanning (IOS) may offer alternatives to conventional impression making. PURPOSE: The purpose of this in vitro study was to assess the accuracy and passive fit of IOS with prefabricated aids, SPG, and open tray impression (OI) for CIFDPs with different implant distributions. MATERIAL AND METHODS: Three definitive casts with 4 parallel implants (4-PARA), 4 inclined implants (4-INCL), and 6 parallel implants (6-PARA) were fabricated. Three recording techniques were tested: IOS with prefabricated aids, SPG, and OI. The best and the worst scans were selected to fabricate 18 milled aluminum alloy frameworks. The trueness and precision of distance deviation (∆td and ∆pd), angular deviation (∆tθand ∆pθ), root mean square errors (∆tRMS for ∆pRMS), and passive fit score of frameworks were recorded. Two-way ANOVA was applied. RESULTS: SPG showed the best trueness and precision (95%CI of ∆td/∆tθ/∆tRMS, 31 to 39 µm, 0.22 to 0.28 degrees, 20 to 23 µm; 95%CI of ∆pd/∆pθ/∆pRMS, 9 to 11 µm, 0.06 to 0.08 degrees, 8 to 10 µm), followed by OI (61 to 83 µm, 0.33 to 0.48 degrees, 28 to 48 µm; 66 to 81 µm, 0.29 to 0.38 degrees, 32 to 41 µm) and IOS (143 to 193 µm, 0.37 to 0.50 degrees, 81 to 96 µm; 89 to 111 µm, 0.27 to 0.31 degrees, 51 to 62 µm). Tilted implants were associated with increased distance deviation. Increased implant number was associated with improved recording precision. The passive fit of frameworks was negatively correlated with the RMS error, and the correlation coefficient was -0.65 (P=.003). CONCLUSIONS: SPG had the best accuracy. Implant distributions affected implant precision. The RMS error can be used to evaluate the passive fit of frameworks.

Assessing cognitive impairment and disability in older adults through the lens of whole brain white matter patterns.

INTRODUCTION: This study aimed to explore the potential of whole brain white matter patterns as novel neuroimaging biomarkers for assessing cognitive impairment and disability in older adults. METHODS: We conducted an in-depth analysis of magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) scans in 454 participants, focusing on white matter patterns and white matter inter-subject variability (WM-ISV). RESULTS: The white matter pattern ensemble model, combining MRI and amyloid PET, demonstrated a significantly higher classification performance for cognitive impairment and disability. Participants with Alzheimer's disease (AD) exhibited higher WM-ISV than participants with subjective cognitive decline, mild cognitive impairment, and vascular dementia. Furthermore, WM-ISV correlated significantly with blood-based biomarkers (such as glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]), and cognitive function and disability scores. DISCUSSION: Our results suggest that white matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making and determining cognitive impairment and disability. HIGHLIGHTS: The ensemble model combined both magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) and demonstrated a significantly higher classification performance for cognitive impairment and disability. Alzheimer's disease (AD) revealed a notably higher heterogeneity compared to that in subjective cognitive decline, mild cognitive impairment, or vascular dementia. White matter inter-subject variability (WM-ISV) was significantly correlated with blood-based biomarkers (glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]) and with the polygenic risk score for AD. White matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making processes and determining cognitive impairment and disability.

Integrated image-based deep learning and language models for primary diabetes care.

Primary diabetes care and diabetic retinopathy (DR) screening persist as major public health challenges due to a shortage of trained primary care physicians (PCPs), particularly in low-resource settings. Here, to bridge the gaps, we developed an integrated image-language system (DeepDR-LLM), combining a large language model (LLM module) and image-based deep learning (DeepDR-Transformer), to provide individualized diabetes management recommendations to PCPs. In a retrospective evaluation, the LLM module demonstrated comparable performance to PCPs and endocrinology residents when tested in English and outperformed PCPs and had comparable performance to endocrinology residents in Chinese. For identifying referable DR, the average PCP's accuracy was 81.0% unassisted and 92.3% assisted by DeepDR-Transformer. Furthermore, we performed a single-center real-world prospective study, deploying DeepDR-LLM. We compared diabetes management adherence of patients under the unassisted PCP arm (n = 397) with those under the PCP+DeepDR-LLM arm (n = 372). Patients with newly diagnosed diabetes in the PCP+DeepDR-LLM arm showed better self-management behaviors throughout follow-up (P < 0.05). For patients with referral DR, those in the PCP+DeepDR-LLM arm were more likely to adhere to DR referrals (P < 0.01). Additionally, DeepDR-LLM deployment improved the quality and empathy level of management recommendations. Given its multifaceted performance, DeepDR-LLM holds promise as a digital solution for enhancing primary diabetes care and DR screening.

Sex-Specific Risk Factors and Clinical Dementia Outcomes for White Matter Hyperintensities in a large South Korean Cohort.

Objective: White matter hyperintensities (WMH) on brain MRI images are the most common feature of cerebral small vessel disease (CSVD). Studies have yielded divergent findings on the modifiable risk factors for WMH and WMH's impact on cognitive decline. Mounting evidence suggests sex differences in WMH burden and subsequent effects on cognition. Thus, we aimed to identify sex-specific modifiable risk factors for WMH. We then explored whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes. Methods: Participants aged 49-89 years were recruited at memory clinics and underwent a T2-weighted fluid-attenuated inversion recovery (FLAIR) 3T MRI scan to measure WMH volume. Participants were then recruited for two additional follow-up visits, 1-2 years apart, where clinical dementia rating sum of boxes (CDR-SB) scores were measured. We first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. We additionally tested which risk factors were significant when stratified by sex. We then tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific. Results: The study utilized data from 713 participants (241 males, 472 females) with a mean age of 72.3 years and 72.8 years for males and females, respectively. 57.3% and 59.5% of participants were diagnosed with mild cognitive impairment (MCI) for males and females, respectively. 40.7% and 39.4% were diagnosed with dementia for males and females, respectively. Of the 713 participants, 181 participants had CDR-SB scores available for three longitudinal time points. Compared to males, females showed stronger association of age to WMH volume. Type 2 Diabetes was associated with greater WMH burden in females but not males. Finally, baseline WMH burden was associated with worse clinical dementia outcomes longitudinally in females but not in males. Discussion: Elderly females have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Additionally, females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the consequences of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies. Clinical trial registration: The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391). Registration Date 2018/12/14.

Long-term outcomes of CNS WHO grade 2 oligodendroglioma in adult patients: a single-institution experience.

PURPOSE: Oligodendrogliomas (ODGs) are a subtype of diffuse lower-grade gliomas with overall survival of > 10 years. This study aims to analyze long-term outcomes and identify prognostic factors in patients with WHO grade 2 ODG. METHODS: We retrospectively reviewed 138 adult patients diagnosed with 1p/19q co-deleted ODG who underwent surgical resection or biopsy between 1994 and 2021, analyzing clinical data, treatment details, and outcomes. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were utilized to identify significant prognostic factors. RESULTS: In the gross total resection (GTR) group, 63 (45.7%) underwent observation and 5 (3.6%) received postoperative treatment; in the non-GTR group, 37 (26.8%) were observed and 33 (23.9%) received postoperative treatment. The median PFS and OS were 6.8 and 18.4 years, respectively. Between adjuvant treatment and observation, there was no significant difference in PFS or OS. However, GTR or STR with less than 10% residual tumor exhibited significantly better PFS and OS compared to PR or biopsy (p = 0.022 and 0.032, respectively). Multivariate analysis revealed that contrast enhancement on MRI was associated with worse PFS (HR = 2.36, p < 0.001) and OS (HR = 5.89, p = 0.001). And the presence of seizures at presentation was associated with improved OS (HR = 0.28, p = 0.006). CONCLUSION: This study underscores favorable long-term outcomes for patients with 1p/19q co-deleted ODG WHO grade 2. Our findings indicate that the EOR plays a crucial role as a significant prognostic factor in enhancing PFS and OS outcomes in WHO grade 2 ODG.

Multimodal Machine Learning-Based Marker Enables Early Detection and Prognosis Prediction for Hyperuricemia.

Hyperuricemia (HUA) has emerged as the second most prevalent metabolic disorder characterized by prolonged and asymptomatic period, triggering gout and metabolism-related outcomes. Early detection and prognosis prediction for HUA and gout are crucial for pre-emptive interventions. Integrating genetic and clinical data from 421287 UK Biobank and 8900 Nanfang Hospital participants, a stacked multimodal machine learning model is developed and validated to synthesize its probabilities as an in-silico quantitative marker for hyperuricemia (ISHUA). The model demonstrates satisfactory performance in detecting HUA, exhibiting area under the curves (AUCs) of 0.859, 0.836, and 0.779 within the train, internal, and external test sets, respectively. ISHUA is significantly associated with gout and metabolism-related outcomes, effectively classifying individuals into low- and high-risk groups for gout in the train (AUC, 0.815) and internal test (AUC, 0.814) sets. The high-risk group shows increased susceptibility to metabolism-related outcomes, and participants with intermediate or favorable lifestyle profiles have hazard ratios of 0.75 and 0.53 for gout compared with those with unfavorable lifestyles. Similar trends are observed for other metabolism-related outcomes. The multimodal machine learning-based ISHUA marker enables personalized risk stratification for gout and metabolism-related outcomes, and it is unveiled that lifestyle changes can ameliorate these outcomes within high-risk group, providing guidance for preventive interventions.

Assessment of ATP metabolism to adenosine by ecto-nucleotidases carried by tumor-derived small extracellular vesicles.

Immunosuppression is a hallmark of cancer progression. Tumor-derived small extracellular vesicles (sEV), also known as TEX, produce adenosine (ADO) and can mediate tumor-induced immunosuppression.Here, the ATP pathway of ADO production (ATP →  ADP →  AMP →  ADO) by ecto-nucleotidases carried on the sEV surface was evaluated by a method using N6-etheno-ATP (eATP) and N6-etheno-AMP (eAMP) as substrates for enzymatic activity. The "downstream" N6-etheno-purines (ePurines) were measured by high performance liquid chromatography with fluorescence detection (HPLC-FL).Human melanoma cell-derived TEX (MTEX) metabolized eATP to N6-etheno-ADP (eADP), eAMP and N6-etheno-Adenosine (eADO) more robustly than control keratinocyte cell-derived sEV (CEX); due to accelerated conversion of eATP to eADP and eADP to eAMP. MTEX and CEX similarly metabolized eAMP to eADO. Blocking of the ATP pathway with the selective CD39 inhibitor ARL67156 or pan ecto-nucleotidase inhibitor POM-1 normalized the ATP pathway but neither inhibitor completely abolished it. In contrast, inhibition of CD73 by PSB12379 or AMPCP abolished eADO formation by both MTEX and CEX, suggesting that targeting CD73 is the preferred approach to eliminating ADO produced by ecto-nucleotidases located on the sEV surface.The noninvasive, sensitive, and specific assay assessing ePurine metabolism ± ecto-nucleotidase inhibitors in TEX enables the personalized identification of ecto-nucleotidase activity primarily involved in ADO production in patients with cancer. The assay could guide precision medicine by determining which purine is the preferred target for inhibitory therapeutic interventions.

Rare infiltrative primary hepatic angiosarcoma: A case report and review of literature.

BACKGROUND: The most primary sites of angiosarcoma are the skin, breast gland, and soft tissues. Primary hepatic angiosarcoma (PHA) is a rare malignant tumor of mesothelial tissue originating from the liver. PHA often presents with multiple intrahepatic foci or metastasis at the time of presentation due to its nonspecific clinical presentation and highly aggressive nature. There are no established or effective treatment guidelines for PHA, so early detection and early treatment are of great value for patient survival. Unfortunately, there is a paucity of literature on the imaging features of PHA, making the diagnosis and treatment of this disease a considerable challenge. CASE SUMMARY: In this case report, we present a 59-year-old man who initially presented with abdominal pain and radiating pain in the right shoulder. Magnetic resonance imaging and positron emission tomography-computed tomography revealed multiple intrahepatic nodules that needed to be differentiated from tumors of vascular epithelial origin and tumors with progressive enhancement features, and signs of tumor metastasis were assessed. The patient was then subjected to contrast-enhanced ultrasonography (CEUS) to further clarify the extent of tumor infiltration and the state of microcirculatory perfusion. The manifestations observed on CEUS were similar to the classical characteristic presentation of hepatocellular carcinoma, called "quick wash-in and quick wash-out". In addition, CEUS showed that the lesion exhibited gradual infiltration and growth along the liver pedicle structures with no invading blood vessels. Finally, based on pathological and immunohistochemical tests and the above imaging manifestations, it was confirmed that the patient had infiltrating PHA, which is a rare pathological type of PHA. The patient underwent transcatheter arterial chemoembolization and chemotherapy. Four months after the onset of symptoms, the follow-up radiological examination revealed poor treatment efficacy and rapid deterioration. CONCLUSION: This case report complements the imaging modalities of a rare infiltrative PHA, in which CEUS and quantitative analysis are found to offer substantial advantages in characterizing the microcirculatory perfusion of the lesion, providing clinicians with diagnostic information at the earliest opportunity to make a diagnosis and develop a treatment strategy to prolong the patient survival.

Comparison of Sonazoid-Contrast­Enhanced Ultrasound and Gd­EOB­DTPA­Enhanced MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVE: This study aims to evaluate and compare the predictive accuracy of Sonazoid-contrast-enhanced ultrasound (CEUS) and Gd-EOB-DTPA-enhanced MRI for detecting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: In this single-center prospective study, we included 64 patients with histopathologically confirmed single HCC lesions. Based on post-operative pathologic data, patients were categorized into two groups: those with MVI (n = 21) and those without MVI (n = 43). The diagnostic efficacy of CEUS was compared with that of MRI in predicting MVI. RESULTS: Multifactorial analysis revealed that US features (tumor size > 4.35 cm, peritumoral enhancement, post-vascular ring enhancement, peak energy in the arterial phase of the difference between the margin area of HCC and distal liver parenchyma <-1.0 × 106 a.u), MRI features (rim enhancement, irregular tumor margin, and the halo sign) were all independent predictors of MVI (p < 0.05). The sensitivity and specificity of CEUS features in predicting MVI ranged from 61.9% to 86.4% and from 42.9% to 71.4%, respectively. For MRI features, the sensitivity and specificity ranged from 33.3% to 76.3% and from 54.7% to 90.5%, respectively. No statistically significant differences were observed in the area under the curve between CEUS and MRI (p > 0.05). Notably, peak energy of the difference showed the highest sensitivity at 86.4%, while the halo sign in MRI exhibited the highest specificity at 90.5%. CONCLUSION: Sonazoid-CEUS and Gd-EOB-DTPA-enhanced MRI demonstrate potential in predicting MVI in HCC lesions. Notably, CEUS showed higher sensitivity, whereas MRI displayed greater specificity in predicting MVI.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy.

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Impact of surface chemical treatment in surgical regenerative treatment of ligature-induced peri-implantitis: A canine study.

BACKGROUND: Implant surface decontamination is a critical step in peri-implantitis treatment. The aim of this study was to assess the effect chemotherapeutic agents have on reosseointegration after treatment on ligature-inducted peri-implantitis. METHODS: Six male canines had 36 implants placed and ligatures were placed around them for 28 weeks to establish peri-implantitis. The peri-implant defects were randomly treated by 1 of 3 methods: 0.12% chlorhexidine (CHX test group), 1.5% sodium hypochlorite (NaOCl test group), or saline (Control group). Sites treated with NaOCl and CHX were grafted with autogenous bone, and all sites then either received a collagen membrane or not. Histology sections were obtained at 6 months postsurgery to assess percentage of reosseointegration. RESULTS: Thirty-five implants were analyzed (CHX: 13; NaOCl: 14; Control:8). NaOCl-treated sites demonstrated reosseointegration with direct bone-to-implant-contact on the previously contaminated surfaces (42% mean reosseointegration), which was significantly higher than Controls (p < 0.05). Correspondingly, clinical improvement was noted with a significant reduction in probing depth from 5.50 ± 1.24 mm at baseline to 4.46 ± 1.70 mm at 6-months postsurgery (p = 0.006). CHX-treated sites demonstrated a nonsignificant reosseointegration of 26% (p > 0.05); however, in the majority of cases, the new bone growth was at a distance from the implant surface without contact. Probing depths did not improve in the CHX group. The use of membrane did not influence reosseointegration or probing depths (all p > 0.05). CONCLUSION: Titanium implants with peri-implantitis have the capacity to reosseointegrate following regenerative surgery. However, treatment response is contingent upon the chemotherapeutic agent selection. Additional chemical treatment with 1.5% NaOCl lead to the most favorable results in terms of changes in defect depth and percentage of reosseointegration as compared to CHX, which may hinder reosseointegration.

Assessing the Utility, Impact, and Adoption Challenges of an Artificial Intelligence-Enabled Prescription Advisory Tool for Type 2 Diabetes Management: Qualitative Study.

BACKGROUND: The clinical management of type 2 diabetes mellitus (T2DM) presents a significant challenge due to the constantly evolving clinical practice guidelines and growing array of drug classes available. Evidence suggests that artificial intelligence (AI)-enabled clinical decision support systems (CDSSs) have proven to be effective in assisting clinicians with informed decision-making. Despite the merits of AI-driven CDSSs, a significant research gap exists concerning the early-stage implementation and adoption of AI-enabled CDSSs in T2DM management. OBJECTIVE: This study aimed to explore the perspectives of clinicians on the use and impact of the AI-enabled Prescription Advisory (APA) tool, developed using a multi-institution diabetes registry and implemented in specialist endocrinology clinics, and the challenges to its adoption and application. METHODS: We conducted focus group discussions using a semistructured interview guide with purposively selected endocrinologists from a tertiary hospital. The focus group discussions were audio-recorded and transcribed verbatim. Data were thematically analyzed. RESULTS: A total of 13 clinicians participated in 4 focus group discussions. Our findings suggest that the APA tool offered several useful features to assist clinicians in effectively managing T2DM. Specifically, clinicians viewed the AI-generated medication alterations as a good knowledge resource in supporting the clinician's decision-making on drug modifications at the point of care, particularly for patients with comorbidities. The complication risk prediction was seen as positively impacting patient care by facilitating early doctor-patient communication and initiating prompt clinical responses. However, the interpretability of the risk scores, concerns about overreliance and automation bias, and issues surrounding accountability and liability hindered the adoption of the APA tool in clinical practice. CONCLUSIONS: Although the APA tool holds great potential as a valuable resource for improving patient care, further efforts are required to address clinicians' concerns and improve the tool's acceptance and applicability in relevant contexts.

Small extracellular vesicles in plasma carry luminal cytokines that remain undetectable by antibody-based assays in cancer patients and healthy donors.

Background: Small (30-150nm) extracellular vesicles (sEV), also known as exosomes, play a key role in cell-to-cell signaling. They are produced by all cells, circulate freely and are present in all body fluids. Evidence indicates that cytokines are present on the surface and/or in the lumen of sEV. The contribution of intravesicular cytokines to cytokine levels in plasma are unknown. Methods: sEV were isolated by ultrafiltration/size exclusion chromatography from pre-cleared plasma obtained from patients with head and neck squamous cell carcinoma (HNSCC) and healthy donors (HDs). Multiplex immunoassays were used to measure cytokine levels in paired untreated and detergent-treated (0.5% Triton X-100) plasma and plasma-derived detergent-treated sEV. Non-parametric tests were used to assess differences in cytokine levels. Results: The presence of cytokines in sEV isolated from patients' and HDs' plasma was confirmed by immunoblots and on-bead flow cytometry. sEV-associated cytokines were functional in various in vitro assays. Levels of cytokines in sEV varied among the HNSCC patients and were generally significantly higher than the levels observed in sEV from HDs. Compared to untreated plasma, levels for the majority (40/51) of the evaluated proteins were significantly higher in detergent-treated plasma (P<0.0001-0.03). In addition, levels of 24/51 proteins in sEV, including IL6, TNFRII, IL-17a, IFNa and IFNg, were significantly positively correlated with the difference between levels detected in detergent-treated plasma and untreated plasma. Discussion: The data indicate that sEV-associated cytokines account for the differences in cytokine levels measured in detergent-treated versus untreated plasma. Ab-based assays using untreated plasma detect only soluble cytokines and miss cytokines carried in the lumen of sEV. Permeabilization of sEV with a mild detergent allows for Ab-based detection of sEV-associated and soluble cytokines in plasma. The failure to detect cytokines carried in the sEV lumen leads to inaccurate estimates of cytokine levels in body fluids.

Single-cell RNA sequencing revealed the role of the Th17 pathway in the development of anti- human leukocyte antigen antibodies in a highly sensitized mouse model.

Background: The aim of this study is to investigate the specific pathway involved in human leukocyte antigen (HLA) sensitization using single-cell RNA-sequencing analysis and an allo-sensitized mouse model developed with an HLA.A2 transgenic mouse. Methods: For sensitization, wild-type C57BL/6 mouse received two skin grafts from C57BL/6-Tg(HLA-A2.1)1Enge/J mouse (allogeneic mouse, ALLO). For syngeneic control (SYN), skin grafts were transferred from C57BL/6 to C57BL/6. We performed single-cell RNA-sequencing analysis on splenocytes isolated from ALLO and SYN and compared the gene expression between them. Results: We generated 9,190 and 8,890 single-cell transcriptomes from ALLO and SYN, respectively. Five major cell types (B cells, T cells, natural killer cells, macrophages, and neutrophils) and their transcriptome data were annotated according to the representative differentially expressed genes of each cell cluster. The percentage of B cells was higher in ALLO than it was in SYN. Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the highly expressed genes in the B cells from ALLO were mainly associated with antigen processing and presentation pathways, allograft rejection, and the Th17 cell differentiation pathway. Upregulated genes in the T cells of ALLO were involved in the interleukin (IL)-17 signaling pathway. The ratio of Th17 cluster and Treg cluster was increased in the ALLO. On flow cytometry, the percentage of Th17 (IL-17+/CD4+ T) cells was higher and regulatory T cells (FOXP3+/CD4+ T) was lower in the ALLO compared to those in the SYN. Conclusion: Our results indicate that not only the B cell lineage but also the Th17 cells and their cytokine (IL-17) are involved in the sensitization to HLA.