Pathways and mechanisms of CD4+CD8αα+ intraepithelial T cell development.

The mammalian small intestine epithelium harbors a peculiar population of CD4+CD8αα+ T cells that are derived from mature CD4+ T cells through reprogramming of lineage-specific transcription factors. CD4+CD8αα+ T cells occupy a unique niche in T cell biology because they exhibit mixed phenotypes and functional characteristics of both CD4+ helper and CD8+ cytotoxic T cells. The molecular pathways driving their generation are not fully mapped. However, recent studies demonstrate the unique role of the commensal gut microbiota as well as distinct cytokine and chemokine requirements in the differentiation and survival of these cells. We review the established and newly identified factors involved in the generation of CD4+CD8αα+ intraepithelial lymphocytes (IELs) and place them in the context of the molecular machinery that drives their phenotypic and functional differentiation.

The ion channel TRPA1 is a modulator of the cocaine reward circuit in the nucleus accumbens.

Drug addiction therapies commonly fail because continued drug use promotes the release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential as a target for drug misuse therapies.

The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.

AIMS/HYPOTHESIS: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD. METHODS: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions. RESULTS: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes. CONCLUSIONS/INTERPRETATION: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

Findings from the KNOW-CKD Study indicate that higher systolic blood pressure time in target range is associated with a lower risk of chronic kidney disease progression.

Time-in-target range (TTR) of systolic blood pressure (SBP) is determined by the proportion of time during which SBP remains within a defined optimal range. TTR has emerged as a useful metric for assessing SBP control over time. However, it is uncertain if SBP-TTR can predict the progression of chronic kidney disease (CKD). Here, we investigated the association between SBP-TTR during the first year of enrollment and CKD progression among 1758 participants from the KNOW-CKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). Baseline median estimated glomerular filtration rate (eGFR) was 51.7 ml/min per 1.73 m2. Participants were categorized into four SBP-TTR groups (0%, 1-50%, 51-99%, and 100%). The primary outcome was CKD progression defined as 50% or more decline in eGFR from baseline measurement or the initiation of kidney replacement therapy. During the follow-up period (9212 person-years over a median 5.4 years), the composite outcome occurred in 710 participants. In the multivariate cause-specific hazard model, a one-standard deviation increase in SBP-TTR was associated with an 11% lower risk of the composite outcome with hazard ratio, 0.89 (95% confidence interval, 0.82-0.97). Additionally, compared to patients with SBP-TTR 0%, the respective hazard ratios for those with SBP-TTR 1-50%, 51-99%, and 100% were 0.85 (0.68-1.07), 0.76 (0.60-0.96), and 0.72 (0.55-0.94), and the respective corresponding slopes of eGFR decline were -3.17 (-3.66 to -2.69), -3.02 (-3.35 to -2.68), -2.62 (-2.89 to - 2.36), and -2.33 (-2.62 to -2.04) ml/min/1.73 m2. Thus, higher SBP-TTR was associated with a decreased risk of CKD progression in patients with CKD.

Comparative analysis of glymphatic system alterations in multiple sclerosis and neuromyelitis optica spectrum disorder using MRI indices from diffusion tensor imaging.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.

A CT-based Deep Learning Model for Predicting Subsequent Fracture Risk in Patients with Hip Fracture.

Background Patients have the highest risk of subsequent fractures in the first few years after an initial fracture, yet models to predict short-term subsequent risk have not been developed. Purpose To develop and validate a deep learning prediction model for subsequent fracture risk using digitally reconstructed radiographs from hip CT in patients with recent hip fractures. Materials and Methods This retrospective study included adult patients who underwent three-dimensional hip CT due to a fracture from January 2004 to December 2020. Two-dimensional frontal, lateral, and axial digitally reconstructed radiographs were generated and assembled to construct an ensemble model. DenseNet modules were used to calculate risk probability based on extracted image features and fracture-free probability plots were output. Model performance was assessed using the C index and area under the receiver operating characteristic curve (AUC) and compared with other models using the paired t test. Results The training and validation set included 1012 patients (mean age, 74.5 years ± 13.3 [SD]; 706 female, 113 subsequent fracture) and the test set included 468 patients (mean age, 75.9 years ± 14.0; 335 female, 22 subsequent fractures). In the test set, the ensemble model had a higher C index (0.73) for predicting subsequent fractures than that of other image-based models (C index range, 0.59-0.70 for five of six models; P value range, < .001 to < .05). The ensemble model achieved AUCs of 0.74, 0.74, and 0.73 at the 2-, 3-, and 5-year follow-ups, respectively; higher than that of most other image-based models at 2 years (AUC range, 0.57-0.71 for five of six models; P value range, < .001 to < .05) and 3 years (AUC range, 0.55-0.72 for four of six models; P value range, < .001 to < .05). Moreover, the AUCs achieved by the ensemble model were higher than that of a clinical model that included known risk factors (2-, 3-, and 5-year AUCs of 0.58, 0.64, and 0.70, respectively; P < .001 for all). Conclusion In patients with recent hip fractures, the ensemble deep learning model using digital reconstructed radiographs from hip CT showed good performance for predicting subsequent fractures in the short term. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Li and Jaremko in this issue.

Electrochemically Active MoO3/TiN Sulfur Host Inducing Dynamically Reinforced Built-in Electric Field for Advanced Lithium-Sulfur Batteries.

Although various electrocatalysts have been developed to ameliorate the shuttle effect and sluggish Li-S conversion kinetics, their electrochemical inertness limits the sufficient performance improvement of lithium-sulfur batteries (LSBs). In this work, an electrochemically active MoO3/TiN-based heterostructure (MOTN) is designed as an efficient sulfur host that can improve the overall electrochemical properties of LSBs via prominent lithiation behaviors. By accommodating Li ions into MoO3 nanoplates, the MOTN host can contribute its own capacity. Furthermore, the Li intercalation process dynamically affects the electronic interaction between MoO3 and TiN and thus significantly reinforces the built-in electric field, which further improves the comprehensive electrocatalytic abilities of the MOTN host. Because of these merits, the MOTN host-based sulfur cathode delivers an exceptional specific capacity of 2520 mA h g-1 at 0.1 C. Furthermore, the cathode exhibits superior rate capability (564 mA h g-1 at 5 C), excellent cycling stability (capacity fade rate of 0.034% per cycle for 1200 cycles at 2 C), and satisfactory areal capacity (6.6 mA h cm-2) under a high sulfur loading of 8.3 mg cm-2. This study provides a novel strategy to develop electrochemically active heterostructured electrocatalysts and rationally manipulate the built-in electric field for achieving high-performance LSBs.

Difference Between Estimated GFR Based on Cystatin C Versus Creatinine and Incident Atrial Fibrillation: A Cohort Study of the UK Biobank.

RATIONALE & OBJECTIVE: The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) has been suggested to reflect factors distinct from kidney function that are associated with cardiovascular risk. However, the association between eGFRdiff and atrial fibrillation (AF) risk has not been extensively evaluated. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Using data from the UK Biobank, this study included 363,494 participants with measured serum creatinine and cystatin C levels and without a prior diagnosis of AF or a history of related procedures. EXPOSURE: Estimated GFRdiff, calculated as cystatin C-based eGFR minus creatinine-based eGFR. Estimated GFRdiff was also categorized as negative (<-15mL/min/1.73m2), midrange (-15 to 15mL/min/1.73m2), or positive (≥15mL/min/1.73m2). OUTCOME: Incident AF. ANALYTICAL APPROACH: Subdistribution hazard models were fit, treating death that occurred before development of AF as a competing event. RESULTS: During the median follow-up period of 11.7 years, incident AF occurred in 18,994 (5.2%) participants. In the multivariable-adjusted model, participants with a negative eGFRdiff had a higher risk of incident AF (subdistribution HR [SHR], 1.25 [95% CI, 1.20-1.30]), whereas participants with a positive eGFRdiff had a lower risk of AF (SHR, 0.81 [95% CI, 0.77-0.87]) compared with those with a midrange eGFRdiff. When eGFRdiff was treated as a continuous variable in the adjusted model, every 10mL/min/1.73m2 higher eGFRdiff was associated with a 0.90-fold decrease in the risk of incident AF. LIMITATIONS: A single measurement of baseline serum creatinine and cystatin C levels. CONCLUSIONS: The difference between cystatin C- and creatinine-based eGFRs was associated with the risk of AF development. A higher eGFRdiff was associated with a lower risk of AF. These findings may have implications for the management of patients at risk of incident AF. PLAIN-LANGUAGE SUMMARY: The difference between cystatin C-based estimated glomerular filtration rate (eGFR) and creatinine-based eGFR has recently gained attention as a potential indicator of cardiovascular outcomes influenced by factors other than kidney function. This study investigated the association between the differences in 2 eGFRs (cystatin C-based eGFR minus creatinine-based eGFR) and incident atrial fibrillation (AF) among>340,000 participants from the UK Biobank Study. Compared with those with a near zero eGFR difference, participants with a negative eGFR difference had a higher risk of AF, while those with a positive eGFR difference had a lower risk. These findings suggest that measuring eGFR differences may help identify individuals at a higher risk of developing AF.

Plasma Levels of Polyunsaturated Fatty Acids and Adverse Kidney Outcomes.

RATIONALE & OBJECTIVE: Many studies have reported polyunsaturated fatty acids (PUFA) as significant predictors of cardiovascular disease, but little is known about the relationship between PUFA levels and chronic kidney disease (CKD). This study explored this relationship among individuals with and without CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 73,419 participants without CKD (cohort 1) and 6,735 participants with CKD (cohort 2) in the UK Biobank Study, with PUFA levels measured between 2007 and 2010. EXPOSURE: Percentage of plasma PUFA, omega-3 fatty acid (FA), omega-6 FA, docosahexaenoic acid (DHA), and linoleic acid relative to total FA. OUTCOME: Incident CKD for cohort 1 and incident kidney failure requiring replacement therapy (KFRT) for cohort 2. ANALYTICAL APPROACH: Cox proportional hazards regression analyses, including a cause-specific competing risk model. RESULTS: In cohort 1, individuals with higher quartiles of plasma PUFA levels had healthier lifestyles and fewer comorbidities. During 841,007 person-years of follow-up (median 11.9 years), incident CKD occurred in 4.5% of participants (incidence rate, 39.1 per 10,000 person-years). For incident CKD in cohort 1, the adjusted cause-specific hazard ratios for quartiles 2, 3, and 4 were 0.83 (95% CI, 0.75-0.92), 0.85 (95% CI, 0.76-0.96), 0.71 (95% CI, 0.62-0.82), respectively, compared with quartile 1. This inverse relationship was consistently observed for all PUFA types. In cohort 2, although total PUFA levels were not associated with KFRT, higher PUFA subtype levels of DHA were associated with a lower risk of KFRT. LIMITATIONS: Observational design and limited generalizability to individuals with higher disease severity; no data on eicosapentaenoic acid. CONCLUSIONS: Among individuals without CKD, higher plasma PUFA levels and all 4 PUFA components were associated with a lower risk of incident CKD. In individuals with CKD, only the omega-3 component of PUFA, DHA, was associated with a lower risk of KFRT. PLAIN-LANGUAGE SUMMARY: Low amounts of polyunsaturated fatty acids (PUFA) in the blood are suspected of increasing the chances of heart disease, but it is not known whether the PUFA relates to kidney disease occurrence. In a large group without kidney disease in the United Kingdom, people with higher levels of PUFA in their blood tended to have a lower risk of developing kidney disease compared to those with lower PUFA levels. This relationship was consistently observed for all PUFA types. However, in the group with kidney disease, only higher levels of docosahexaenoic acid, a subtype of PUFAs, were associated with a lower risk of developing severe kidney problems that required kidney replacement therapy. These findings suggest that higher levels of PUFA, found in certain healthy fats, might protect against the development of kidney disease in the general population. As kidney function declines, only the docosahexaenoic acid, a subtype of PUFA, appears to be associated with preserved kidney function.

The ever-expanding role of cytokine receptor DR3 in T cells.

Death Receptor 3 (DR3) is a cytokine receptor of the Tumor Necrosis Factor receptor superfamily that plays a multifaceted role in both innate and adaptive immunity. Based on the death domain motif in its cytosolic tail, DR3 had been proposed and functionally affirmed as a trigger of apoptosis. Further studies, however, also revealed roles of DR3 in other cellular pathways, including inflammation, survival, and proliferation. DR3 is expressed in various cell types, including T cells, B cells, innate lymphocytes, myeloid cells, fibroblasts, and even outside the immune system. Because DR3 is mainly expressed on T cells, DR3-mediated immune perturbations leading to autoimmunity and other diseases were mostly attributed to DR3 activation of T cells. However, which T cell subset and what T effector functions are controlled by DR3 to drive these processes remain incompletely understood. DR3 engagement was previously found to alter CD4 T helper subset differentiation, expand the Foxp3+ Treg cell pool, and maintain intraepithelial γδ T cells in the gut. Recent studies further unveiled a previously unacknowledged aspect of DR3 in regulating innate-like invariant NKT (iNKT) cell activation, expanding the scope of DR3-mediated immunity in T lineage cells. Importantly, in the context of iNKT cells, DR3 ligation exerted costimulatory effects in agonistic TCR signaling, unveiling a new regulatory framework in T cell activation and proliferation. The current review is aimed at summarizing such recent findings on the role of DR3 on conventional T cells and innate-like T cells and discussing them in the context of immunopathogenesis.

Reference-free in situ rapid regional calibration of phase-only spatial light modulators.

Spatial light modulators (SLMs) have become an indispensable element in modern optics for their versatile performance in many applications. Among various types of SLMs, such as digital micromirror devices (DMD), liquid crystal-based phase-only spatial light modulators (LC-SLMs), and deformable mirrors (DM), LC-SLMs are often the method of choice due to their high efficiency, precise phase modulation, and abundant number of effective pixels. In general, for research grade applications, an additional SLM calibration step is required due to fabrication imperfection resulting in non-flat liquid crystal panels and varying phase responses over the SLM area. Here, we demonstrate a straightforward approach for reference-free orthogonal calibration of an arbitrary number of SLM subregions which only requires the same measurement time as global calibration. The proposed method requires minimal optical elements and can be applied to any optical setup as is. As a benchmark performance test, we achieved a 2.2-fold enhancement in correction efficiency for wavefront shaping through scattering media utilizing the calibrated 2160 subregions of the SLM, in comparison with a single global look-up table (LUT).

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

Donor fat-to-muscle ratio and kidney transplant outcomes: A proposition of metabolic memory.

AIMS: The impact of donor abdominal fat-to-muscle ratio (FMR) on kidney transplant (KT) outcomes was assessed. Given the transient nature of the donor's metabolic environment in transplant recipients, this study investigated the capacity of body composition to induce metabolic memory effects. MATERIALS AND METHODS: KT patients (n = 895) who received allografts from living donors (2003-2013) were included. Donor fat and muscle were quantified using pre-KT abdominal computed tomography scans. Patients were categorised into donor FMR tertiles and followed up for graft outcomes. Additionally, genome-wide DNA methylation analysis was performed on 28 kidney graft samples from KT patients in the low- and high-FMR groups. RESULTS: Mean recipient age was 42.9 ± 11.4 years and 60.9% were males. Donor FMR averaged 1.67 ± 0.79. Over a median of 120.9 ± 42.5 months, graft failure (n = 127) and death-censored graft failure (n = 109) were more frequent in the higher FMR tertiles. Adjusted hazard ratios for the highest versus lowest FMR tertile were 1.71 (95% CI, 1.06-2.75) for overall graft failure and 1.90 (95% CI, 1.13-3.20) for death-censored graft failure. Genome-wide DNA methylation analysis identified 58 differentially methylated regions (p < 0.05, |Δß| > 0.2) and 35 genes showed differential methylation between the high- (FMR >1.91) and low-FMR (FMR <1.27) groups. CONCLUSIONS: Donors with increased fat and reduced muscle composition may negatively impact kidney allograft survival in recipients, possibly through the transmission of epigenetic changes, implying a body-composition-related metabolic memory effect.

Utility of Prostate Health Index Density for Biopsy Strategy in Biopsy-Naïve Patients With PI-RADS v2.1 Category 3 Lesions.

BACKGROUND: Category 3 lesions in PI-RADSv2.1 pose diagnostic challenges, complicating biopsy decisions. Recent biomarkers like prostate health index (PHI) have shown higher specificity in detecting clinically significant prostate cancer (csPCa) than prostate-specific antigen (PSA). Yet their integration with MRI remains understudied. PURPOSE: To evaluate the utility of PSA and PHI with its derivatives for detecting csPCa in biopsy-naïve patients with category 3 lesion on initial prostate MRI scan. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-three biopsy-naïve patients who underwent MRI, PSA, and PHI testing, followed by both targeted and systematic biopsies. FIELD STRENGTH/SEQUENCE: Turbo spin-echo T2-weighted imaging, diffusion-weighted single-shot echo-planar imaging, and dynamic contrast-enhanced T1-weighted fast field echo sequence imaging in 3 T. ASSESSMENT: PHI density (PHID) and PSA density (PSAD) derived by dividing serum PHI and PSA with prostate volume (MRI based methodology suggested by PI-RADSv2.1). Risk-stratified models to evaluate the utility of markers in triaging patients for biopsy, including low-, intermediate-, and high-risk groups. STATISTICAL TESTS: Independent t-test, Mann-Whitney U test, Mantel-Haenszel test, generalized estimating equation, and receiver operating characteristic (ROC) curve analysis were used. Statistical significance defined as P < 0.05. RESULTS: CsPCa was found in 16.6% (32/193) of patients. PHID had the highest area under the ROC curve (AUROC) of 0.793, followed by PHI of 0.752, PSAD of 0.750, and PSA of 0.654. PHID with two cut-off points (0.88/mL and 1.82/mL) showed the highest potential biopsy avoidance of 47.7% (92/193) with 5% missing csPCa, and the lowest intermediate-risk group (borderline decision group) at 38.9% (75/193), compared to PSA and PHI. DATA CONCLUSION: PHID demonstrated better potential in triaging patients with category 3 lesions, possibly aiding more selective and confident biopsy decisions for csPCa detection, than traditional markers. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Novel self-expandable stent-based endobiliary radiofrequency ablation for unresectable malignant biliary obstruction.

BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) is an emerging endoscopic palliative adjunctive therapy used for the local treatment of unresectable malignant biliary obstruction (MBO). However, irregular ablation ranges caused by insufficient electrode-to-bile duct contact pose a significant obstacle. We investigated the feasibility of a self-expandable stent (SES)-based electrode with a customized RFA generator in the porcine liver and common bile duct (CBD). METHODS: An SES-RFA system with polarity switching was developed to perform endobiliary RFA. The ablation ranges of 20 ablation protocols were evaluated to validate the feasibility of the newly developed RFA system in the porcine liver. Nine of 20 ablation protocols were selected for evaluation in the porcine CBD with cholangiography, endoscopy, and histologic and immunohistochemical analysis. RESULTS: The SES-RFA system with polarity switching was successfully constructed and demonstrated high accuracy and reproducibility. The ablation area was clearly identified between the 2 SESs. The ablation ranges and degree of mucosal damage, including terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling-positive and heat shock protein 70-positive depositions, increased proportionally with ablation protocols in the porcine liver and CBD (all P < .05). Ablation length and depth linearly increased with ablation protocols from 8.74 ± .25 to 31.25 ± .67 mm and 1.61 ± .09 to 11.94 ± .44 mm, respectively. CONCLUSIONS: The SES-RFA system with polarity switching between electrodes provided an even circumferential area of ablation and enhanced ablation depth between the electrodes. This novel endobiliary RFA system is a promising modality for local ablation in patients with unresectable MBO.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Neglected but Clinically Relevant Allergens in Korea.

PURPOSE OF REVIEW: Allergy diagnostics and immunotherapeutics in Asia heavily rely on imported products from Western countries, raising concerns about the accuracy and efficacy of these products for the management of Asian allergy patients. RECENT FINDINGS: Recent advancements in allergen research have led to the identification and characterization of novel allergens from indigenous Korean species. While some allergens share homology with well-known allergens, others lack counterparts in imported allergen extracts. Classifying regional allergens in Asia into three categories based on their cross-reactivity with imported allergens offers valuable insights. Highly cross-reactive allergens, such as oak allergens Que m 1 from Quercus mongolica and Que ac 1 from Q. acutissima, can be effectively substituted with the imported allergens. Allergens with partial cross-reactivity, like the Asian needle ant allergen Pac c 3 (Antigen 5), permit limited diagnostic value by the currently available products. Unique allergens, including the Japanese hop allergen Hum j 6 (pectin methylesterase inhibitor) and the silkworm pupa allergen Bomb m 4 (30 kDa hemolymph lipoprotein) lack alternatives in the available product list. Greater attention is needed, particularly for species listed as ecologically invasive in Western regions. Additionally, allergens from domestic fruits and vegetables causing pollen food allergy syndrome require characterization for the development of improved diagnostics.

A multiplex real-time RT-qPCR assay for simultaneous detection of porcine epidemic diarrhea virus, porcine deltacoronavirus, and swine acute diarrhea syndrome coronavirus.

Porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome coronavirus (SADS-CoV) cause intestinal diseases with similar manifestations in suckling piglets. In this study, we developed a multiplex real-time PCR for differential diagnosis of PEDV, PDCoV, and SADS-CoV. The assay demonstrated high specificity with a detection limit of 5 copies/µl for each virus. The assay specifically detected PEDV, PDCoV, and SADS-CoV and excluded all other swine pathogens circulating in pigs. Furthermore, the assay exhibited satisfactory performance in analyzing clinical samples. The data indicate that the newly developed multiplex real-time PCR method can be applied for differential diagnosis of porcine enteric coronaviruses.

The important role of whole-process computed tomography guidance for percutaneous gastrostomy in esophageal cancer patients who are unsuitable for or have had unsuccessful attempts with endoscopic and fluoroscopic gastrostomy.

PURPOSE: To explore the value of clinical application with the whole process computed tomography (CT) guided percutaneous gastrostomy in esophageal tumor patients. MATERIALS AND METHODS: A consecutive series of 32 esophageal tumor patients in whom endoscopic gastrostomy or fluoroscopy guided gastrostomy were considered too dangerous or impossible due to the esophagus complete obstruction, complicate esophageal mediastinal fistula, esophageal trachea fistula or severe heart disease. All of the 32 patients were included in this study from 2 medical center and underwent the gastrostomy under whole process CT guided. RESULTS: All of the gastrostomy procedure was finished successfully under whole process CT guided and the technical success rate was 100%. The average time for each operation was 27 min. No serious complications occurred and the minor complications occurred in 3 patients, including local infection, severe hyperplasia of granulation tissue and tube dislodgment. There were no procedure related deaths. CONCLUSION: The technical success rate of whole process CT guided percutaneous gastrostomy is high and the complication is low. This technique can be used feasible and effectively in some special patients.

Differences in maternal subgingival microbiome between preterm and term births: The MOHEPI study.

AIM: Periodontitis is a potential risk factor for preterm birth (PTB) in women; however, the causal relationship or the exact mechanism remain unknown. This study aimed to compare the oral microbiome features of mothers with full-term birth (FTB) with those who had preterm delivery. METHODS: This study prospectively enrolled 60 women (30 mothers with PTB and 30 mothers with FTB), and subgingival plaque samples were collected and analysed by metagenomic 16S rDNA sequencing. Clinical measurements, including periodontal probing depth, clinical attachment level, modified gingival index (mGI) and plaque index, were performed to determine the periodontal state of the participants. Medical and obstetric data were collected as well. RESULTS: Among the periodontal measurements, mGI score, reflecting the level of gingival inflammation, exhibited a statistically significant association with PTB (adjusted odds ratio 2.705, 95% confidence interval 1.074-6.811, p = .035). When subgroup analysis was conducted based on mean mGI scores (mGI ≥ 2, high inflammation [HI] versus mGI < 2, low inflammation [LI]), microbiome analysis revealed clear distinctions in microbial compositions between PTB and FTB mothers in both the HI and LI groups. Especially in the HI group, alpha diversity exhibited a decreasing trend in PTB mothers compared to FTB mothers. Beta diversity also revealed significant differences between the two groups. In Linear Discriminant Analysis Effect Size analysis, certain anaerobic taxa, including the genera Spirochaetes, Treponema and Porphyromonas, were relatively abundant in the FTB/HI group, whereas the PTB/HI group showed a high abundance of the order Actinomycetales. Network analysis showed that the FTB/HI had relatively stronger connectivity in microbial composition than the PTB/HI group. Dysbiosis ratio of plaque microbiome, in terms of periodontitis, was significantly lower in PTB/HI group compared to FTB/HI group. CONCLUSION: The compositions of maternal subgingival microbiomes differed between PTB and FTB mothers in both the high and low levels of gingival inflammation groups. In the presence of high level of gingival inflammation, dysbiosis in plaque microbiome, in terms of periodontitis, was decreased in PTB mothers compared to FTB mothers.