Foxp and Skor family proteins control differentiation of Purkinje cells from Ptf1a- and Neurog1-expressing progenitors in zebrafish.

Cerebellar neurons, such as GABAergic Purkinje cells (PCs), interneurons (INs) and glutamatergic granule cells (GCs) are differentiated from neural progenitors expressing proneural genes, including ptf1a, neurog1 and atoh1a/b/c. Studies in mammals previously suggested that these genes determine cerebellar neuron cell fate. However, our studies on ptf1a;neurog1 zebrafish mutants and lineage tracing of ptf1a-expressing progenitors have revealed that the ptf1a/neurog1-expressing progenitors can generate diverse cerebellar neurons, including PCs, INs and a subset of GCs in zebrafish. The precise mechanisms of how each cerebellar neuron type is specified remains elusive. We found that genes encoding the transcriptional regulators Foxp1b, Foxp4, Skor1b and Skor2, which are reportedly expressed in PCs, were absent in ptf1a;neurog1 mutants. foxp1b;foxp4 mutants showed a strong reduction in PCs, whereas skor1b;skor2 mutants completely lacked PCs, and displayed an increase in immature GCs. Misexpression of skor2 in GC progenitors expressing atoh1c suppressed GC fate. These data indicate that Foxp1b/4 and Skor1b/2 function as key transcriptional regulators in the initial step of PC differentiation from ptf1a/neurog1-expressing neural progenitors, and that Skor1b and Skor2 control PC differentiation by suppressing their differentiation into GCs.

Systematic Characterization of the Clinical and Pathological Features of Schwannomas Harboring SH3PXD2A::HTRA1 Fusion.

The understanding of schwannoma tumorigenesis has been reshaped by the recent identification of SH3PXD2A::HTRA1 fusion in 10% of intracranial/spinal schwannomas. Nonetheless, pathologic features of schwannomas harboring this fusion, as well as its prevalence outside intracranial/spinal locations, have not been characterized. We screened 215 consecutive schwannomas for their clinicopathologic characteristics and fusion status using reverse-transcriptase polymerase chain reaction (RT-PCR). Among 29 (13.5%) fusion-positive schwannomas, the most prevalent location was peripheral somatic tissue (30.7%, 19/62), followed by spinal/paraspinal (18.4%, 7/38), body cavity/deep structures (10%, 2/20), intracranial (1.3%, 1/75), and viscera (0/13). All 8 cellular, 4 microcystic/reticular, and 3 epithelioid schwannomas were fusion-negative, as were 41/42 nonschwannomatous peripheral nerve sheath tumors. Remarkably, a distinct 'serpentine' palisading pattern, comprising ovoid/plump cells shorter than usual schwannian cells in a hyalinized stroma, was identified in most fusion-positive cases and the schwannomatous component of the only fusion-positive malignant peripheral nerve sheath tumor. To validate this finding, 60 additional cases were collected, including 36 with (≥10% arbitrarily) and 24 without appreciable serpentine histology, of which 29 (80.6%) and 2 (8.3%) harbored the fusion, respectively. With percentages of 'serpentine' areas scored, 10% was determined as the optimal practical cut-off to predict the fusion status (sensitivity, 0.950; specificity, 0.943). Fusion positivity was significantly associated with serpentine histology, smaller tumors, younger patients, and peripheral somatic tissue, while multivariate logistic linear regression analysis only identified serpentine histology and location as independent fusion-predicting factors. RNA in situ hybridization successfully detected the fusion junction, highly concordant with RT-PCR results. Gene expression profiling on 18 schwannomas demonstrated segregation largely consistent with fusion status. Fusion-positive cases expressed significantly higher HTRA1 mRNA abundance, perhaps exploitable as a biomarker. In summary, we systematically characterize a series of 60 SH3PXD2A::HTRA1 fusion-positive schwannomas, showing their distinctive morphology and location-specific prevalence for the first time.

Application of Multi-Channel Synchronized Dynamic Strain Gauges in Monitoring the Neutral Axis Position and Prestress Loss of Box Girder Bridges.

The aim of this paper was to explore the application of multi-channel synchronized dynamic strain gauges in monitoring the neutral axis (N.A.) position of prestressed concrete box girders. The N.A. position has recently been proposed as an indicator for monitoring the health of bridge structures. Laboratory experiments were conducted on a prestressed T-beam under different prestress level conditions to investigate the correlation between the prestress magnitude and the N.A. position. In the development of the multi-channel synchronized dynamic strain gauges, edge computing was employed to significantly reduce the amount of data transmitted from the sensor nodes on-site. In edge computing, only the dynamic strain response caused by the maximum vehicle load in each minute is transmitted. This approach greatly enhances the monitoring efficiency and enables the realization of on-site non-computer-based monitoring systems. The laboratory test results of the prestressed T-beam showed that the N.A. position tends to move slightly downward as the prestress force increases. In other words, when the prestress force decreases due to loss, the N.A. position exhibits a slight upward movement. This study selected a newly constructed prestressed box girder as the subject for on-site measurement of the N.A. position using multi-channel synchronized dynamic strain gauges shortly after the prestress was applied. The on-site monitoring data indeed revealed a gradual upward movement of the N.A. position. This phenomenon confirmed that soon after the completion of prestressed concrete bridges, there is a gradual loss of prestress due to the significant shrinkage and creep effects of the early-age concrete. The on-site monitoring result aligned with the findings from the laboratory experiments, where the N.A. position was observed to move upward as the prestress decreased.

The cementless taper wedge vs. fit-and-fill stem in primary total hip arthroplasty: risk of stem-related complication differs across Dorr types.

INTRODUCTION: The choice between a cementless taper wedge stem and a fit-and-fill stem in total Hip arthroplasty (THA) for various proximal femoral morphological types has not been thoroughly evaluated. This study aimed to compare the risk of stem-related complications between these two stem types in Dorr type A, B, and C femurs. MATERIALS AND METHODS: From January 2015 through April 2021, we retrospectively reviewed 1995 cementless THA procedures. We stratified all procedures into three groups: Dorr type A (N = 360, 18.0%), B (N = 1489, 74.7%) and C (N = 146, 7.3%). The primary outcome domain was stem-related complications, including stem subsidence ≥ 3 mm, intraoperative fracture, periprosthetic fracture and aseptic stem loosening. We performed multivariate regression analysis to compare the risk of stem-related complication between the two stem types. Other factors included age, sex, body mass index, diagnosis, age-adjusted Charlson comorbidity index, stem alignment and canal fill ratio. RESULTS: The incidence of stem-related complications in the taper wedge and fit-and-fill stem groups was 4.4% (N = 15) and 6.5% (N = 107), respectively. Fit-and-fill stems showed an increased risk of stem-related complications (aOR: 9.903, 95% CI: 1.567-62.597) only in Dorr type C femurs. No significant difference in risk was observed in Dorr type A and B femurs. Furthermore, the canal fill ratio at the lesser trochanter, 2 cm and 7 cm below the lesser trochanter, did not exhibit an association with stem-related complications in any Dorr type. CONCLUSIONS: Concerning the risk of stem-related complications, the taper wedge stem was a better choice in Dorr type C femurs. However, there was no difference in risk between the taper wedge stem and fit-and-fill stem in Dorr type A and B femurs.

Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming.

The nucleotide-binding and oligomerization domain, leucine-rich repeats, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1ß secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC-itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases.

Extraskeletal Myxoid Chondrosarcomas: The Uncommon Clinicopathologic Manifestations and Significance of TAF15::NR4A3 Fusion.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.

Characterization of clinical features and comorbidities between bipolar affective disorder with and without depressive episodes.

BACKGROUNDS: A proportion of patients with bipolar disorder (BD) manifests with only unipolar mania (UM). This study examined relevant clinical features and psychosocial characteristics in UM compared with depressive-manic (D-M) subgroups. Moreover, comorbidity patterns of physical conditions and psychiatric disorders were evaluated between the UM and D-M groups. METHODS: This clinical retrospective study (N = 1015) analyzed cases with an average of 10 years of illness duration and a nationwide population-based cohort (N = 8343) followed up for 10 years in the Taiwanese population. UM was defined as patients who did not experience depressive episodes and were not prescribed adequate antidepressant treatment during the disease course of BD. Logistic regression models adjusted for relevant covariates were used to evaluate the characteristics and lifetime comorbidities in the two groups. RESULTS: The proportion of UM ranged from 12.91% to 14.87% in the two datasets. Compared with the D-M group, the UM group had more psychotic symptoms, fewer suicidal behaviors, a higher proportion of morningness chronotype, better sleep quality, higher extraversion, lower neuroticism, and less harm avoidance personality traits. Substantially different lifetime comorbidity patterns were observed between the two groups. CONCLUSIONS: Patients with UM exhibited distinct clinical and psychosocial features compared with patients with the D-M subtype. In particular, a higher risk of comorbid cardiovascular diseases and anxiety disorders is apparent in patients with D-M. Further studies are warranted to investigate the underlying mechanisms for diverse presentations in subgroups of BDs.

Exploring the effects of sudden institutional coercive pressure on digital transformation in colleges from teachers' perspective.

While past technology acceptance studies focus on organization readiness, little is known about the acceptance behavior under sudden institutional coercive pressure. Against COVID-19 and distance teaching, this study explores the relationship between digital transformation readiness, adoption intention, digital transformation success, and sudden institutional coercive pressure based on the readiness research model and institutional theory. Surveying 233 college teachers who participated in distance teaching under COVID-19 in Taiwan for model and hypothesis validation using the partial least square structural equation modeling (PLS-SEM) approach. This result shows that (1) Teacher, social/public, and content readiness are crucial to distance teaching. Individuals, organizational resources, and external stakeholders influence distance teaching success and adoption; and (2) Sudden institutional coercive pressure has a negative moderated effect on teachers' readiness and adoption intention. When teachers are unprepared to implement distance teaching, this unanticipated epidemic and sudden institutional coercive pressure will accelerate and enhance their intention. The study provides government, educational policymakers, and teachers with a better understanding of distance teaching during the COVID-19 pandemic.

Adult NTRK-rearranged spindle cell neoplasms of the viscera: with an emphasis on rare locations and heterologous elements.

NTRK-rearranged mesenchymal neoplasms mostly affect the soft tissues of pediatric patients. Given the responsiveness to selective NTRK inhibitors, it remains critical to identify those ultra-rare cases occurring in the viscera of adults. In five females and two males aged 18-53 years, we characterized visceral mesenchymal tumors harboring TPM3-NTRK1 [uterine cervix (N = 2), pleura, prostate], LMNA-NTRK1 (lung), SQSTM1-NTRK3 (heart), and NTRK3 rearrangement with unknown fusion partner (colon/mesocolon) with RNA sequencing, FISH, RT-PCR, and immunohistochemistry. The tumors exhibited spindled to ovoid/epithelioid or pleomorphic cells, often arranged in fascicles, and were low-to-intermediate-grade and high-grade in three and four cases, respectively. Keloid-like stromal collagen and perivascular hyalinization was noted in five. Adenosarcoma-like appearances were observed in two, manifesting frond-like protrusions in one cervical tumor and phyllodes-like architecture in the prostatic tumor. Abrupt high-grade transformation into pleomorphic liposarcoma was found in another cervical tumor, while the pleural tumor contained intermixed rhabdomyoblasts. Pan-TRK immunostaining was positive in all cases. All cases expressed CD34, while five were S100-positive. CDKN2A homozygous deletion with concomitant p16 loss occurred in 4/7. Whole-exome sequencing identified TP53 mutation (c.672+2T>C, involving a splice site, with concomitant protein loss) in a cervical sarcoma, limited to its heterologous liposarcomatous component. At least moderate pan-TRK immunoreactivity was present in varying proportions of potential pathologic mimics, with BCOR-positive sarcoma (56%, 5/9), undifferentiated uterine sarcoma (50%, 3/6), and spindle cell/sclerosing rhabdomyosarcoma (33%, 2/6) being among the most frequent. This underscored the unsatisfactory specificity of pan-TRK immunohistochemistry and warranted molecular confirmation in the diagnosis of adult NTRK-rearranged visceral mesenchymal neoplasms. The current report highlights the ever-expanding clinicopathologic and genetic spectrum of this entity by describing the unprecedented cardiac and pleural locations and heterologous differentiation, as well as the second NTRK-rearranged "prostatic stromal sarcoma," while substantiating CDKN2A deletion as a frequent occurrence.

Estimations of infiltration factors of diurnal PM2.5 and heavy metals in children's bedrooms.

Children are the sensitive population to fine particulate matter (PM2.5 ) exposure and spend most of their time in bedroom. Infiltration factor (Finf ) can be used to calculate the fraction of total indoor PM2.5 with outdoor origin to increase the accuracy of exposure assessment. However, studies have ignored the diurnal variations of PM2.5 Finf values, and a few studies have estimated Finf values for heavy metals in PM2.5 in children's bedrooms. To calculate the PM2.5 Finf , real-time indoor and outdoor PM2.5 concentrations and occupants' activities were collected in 56 study bedrooms. At 22 of the 56 study bedrooms, PM2.5 samples were also collected for heavy metals analysis. We noted the PM2.5 Finf was higher during the daytime (0.70 ± 0.23) than nighttime (0.54 ± 0.27) during the hot season, and the time of air conditioner use was longer at nighttime. The largest Finf value of heavy metal was V (0.88 ± 0.25), followed by Pb (0.85 ± 0.28), Mn (0.72 ± 0.26), Cr (0.69 ± 0.35), and Zn (0.61 ± 0.32), with a larger variation. Our findings suggest that the estimations of diurnal PM2.5 and heavy metals Finf values are necessary to increase the accuracy of exposure assessment.

Reduced blood flow by laser speckle flowgraphy after 125I-plaque brachytherapy for uveal melanoma.

BACKGROUND: To determine whether reductions in retinal and choroidal blood flow measured by laser speckle flowgraphy are detected after 125I-plaque brachytherapy for uveal melanoma. METHODS: In a cross-sectional study, retinal and choroidal blood flow were measured using laser speckle flowgraphy in 25 patients after treatment with 125I-plaque brachytherapy for uveal melanoma. Flow was analyzed in the peripapillary region by mean blur rate as well as in the entire image area with a novel superpixel-based method. Relationships between measures were determined by Spearman correlation. RESULTS: Significant decreases in laser speckle blood flow were observed in both the retinal and choroidal vascular beds of irradiated, but not fellow, eyes. Overall, 24 of 25 patients had decreased blood flow compared to their fellow eye, including 5 of the 6 patients imaged within the first 6 months following brachytherapy. A significant negative correlation between blood flow and time from therapy was present. CONCLUSIONS: Decreases in retinal and choroidal blood flow by laser speckle flowgraphy were detected within the first 6 months following brachytherapy. Reduced retinal and choroidal blood flow may be an early indicator of microangiographic response to radiation therapy.

Shared decision-making and patient decision aids in choosing first-line targeted therapy for metastatic colorectal cancer in Taiwan.

INTRODUCTION: In Taiwan, given the discrepancy between current treatment guidelines and reimbursement options, patients might require a tool to support their decision-making process when selecting a regimen for metastatic colorectal cancer, especially therapeutic strategies, and subsequent costs, along with efficacy and safety outcomes. Therefore, we developed a patient decision aid (PDA) to support patients in choosing between treatment options recommended based on the current evidence and those reimbursed by the Taiwanese National Health Insurance. METHODS: By carefully reviewing the updated data and then interpreting the clinical tool, we conducted a needs assessment using a serial questionnaire to test for a step-by-step adjustment of the PDA. RESULTS: Patients, their relatives, and medical team members were most concerned about outcomes, such as overall survival, progression-free survival, objective response rate, tumor shrinkage to resectable status, total medical cost, severe gastrointestinal perforation, and severe skin reaction. After a serial alpha test for quality, we performed quantitative evaluation and beta tests, revealing average scores of more than 4 points (on a scale of 1-5) for both perceptibility and utility. CONCLUSIONS: The present findings suggest that PDAs are useful and supplement the shared decision-making practice, helping patients make decisions about preferences and consider the pros and cons of treatment regimens, along with insurance reimbursement options.

Trichomonas infection in pregnant women: a nationwide cohort study.

Trichomoniasis is the most prevalent sexually transmitted infection worldwide, and is associated with adverse pregnancy outcomes. However, Trichomonas vaginalis (TV) has received little public health attention, and only limited data are available on prevalence of TV and other Trichomonas-associated syndromes in pregnant women. This study aimed to determine associations between pregnancy and incident trichomoniasis-related diseases. Data of pregnant women were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. The pregnant cohort included 113,781 women, and cases were randomly matched by age, and index year with those of non-pregnant women (n = 113,781). Risk of incident trichomoniasis-related diseases was also not significantly different between pregnant and non-pregnant women. However, after stratifying by age or level of care, the younger subgroup among pregnant women had a higher risk of incident trichomoniasis-related diseases than did the younger subgroup in non-pregnant women, while the elder subgroup among pregnant women had a lower risk of incident trichomoniasis-related diseases than did the same subgroup in non-pregnant women (all p < 0.05). The higher level of care (medical center) subgroup among pregnant women had a lower risk of incident trichomoniasis-related diseases than did the same subgroup in non-pregnant women. In conclusions, although pregnancy is not significantly associated with risk of trichomoniasis-related diseases, data of the present study support an enhanced high level of medical care for pregnant women, emphasizing the potential of high medical care in reduced incidence of trichomoniasis-related diseases. This may be an effective strategy for reducing various pregnancy complications associated with trichomoniasis-related diseases.

Association between population-based fluoride varnish application services and dental caries experience among schoolchildren in Taiwan.

BACKGROUND/PURPOSE: Taiwan government has provided population-based fluoride varnish application services for all preschool children since July 2004. This study investigated the association providing such services on dental caries experiences among schoolchildren. METHODS: A cross-sectional study was conducted on schoolchildren aged 8-9 years. A questionnaire collected information on sociodemographic background, parents' oral health status, children's oral health-related behavior, and dietary habits. Dental caries was recorded through standardized oral examinations. The number of services was retrieved from the Taiwan National Health Insurance Research Database. Univariate, multivariable linear, and logistic regression analyses were performed. RESULTS: The study involved 1246 children. The mean dental caries indices were 3.97 for decayed, extracted, and filled teeth (deft) and 0.94 for decayed, missing and filled teeth (DMFT). After adjustments for confounding factors, it was revealed that children receiving services were not associated with significantly lower deft and DMFT indices (P > 0.05). The adjusted odds ratio (OR) for untreated primary teeth of children receiving 3 or more services was 0.64 (95% CI = 0.44-0.95) compared with those who received no services (P = 0.025). However, subgroup analyses demonstrated that children in the low-risk group were mainly affected (adjusted OR = 0.36-0.89, P = 0.013). CONCLUSION: This study revealed that children receiving 3 or more services were associated with a 36% decreased risk of having untreated caries in primary dentition, but these children were mainly in the low-risk group. These results illustrate real data that provides dentists and policymakers with valuable information.

Application of Edge Computing in Structural Health Monitoring of Simply Supported PCI Girder Bridges.

This study proposes an innovative method for structural health monitoring of simply supported PCI girder bridges based on dynamic strain and edge computing. Field static and dynamic load tests were conducted on a bridge consisting of a span with newly replaced PCI girders and numerous spans with old PCI girders. Both the static and dynamic test results showed that the flexural rigidity of the old PCI girders decreased significantly due to deterioration. To improve the efficiency of on-site monitoring data transmission and data analysis, this study developed a smart dynamic strain gauge node with the function of edge computing. Continuous data with a sampling frequency of 100 Hz were computed at the sensor node. Among the computed results, only the maximum dynamic strain data caused by the passage of the heaviest vehicle within 1 min were transmitted. The on-site monitoring results indicated that under routine traffic conditions, the dynamic strain response of the new PCI girder was smaller than that of the deteriorated PCI girder. When the monitored dynamic strain response has a tendency to magnify, attention should be paid to the potential prestress loss or other deterioration behaviors of the bridge.

Inverse Association Between Fatty Liver at Baseline Ultrasonography and Remission of Type 2 Diabetes Over a 2-Year Follow-up Period.

BACKGROUND & AIMS: Improvement of fatty liver may be required for remission of type-2 diabetes. However, there is no longitudinal evidence on whether fatty liver reduces the chances for remission of type-2 diabetes. We investigated the association between fatty liver and remission of type-2 diabetes (the primary analysis), and also the association between improvement of fatty liver and remission of type-2 diabetes (the secondary analysis). METHODS: We collected data from 66961 people who underwent screening for type-2 diabetes from 2008 through 2016 at a single center in Japan. The primary analysis included 2567 patients with type-2 diabetes without chronic renal failure or a history of hemodialysis who underwent ultrasonography to detect fatty liver, all of whom had follow-up testing, including blood testing, for a median 24.5 months after the baseline ultrasonography. The secondary analysis included 1833 participants with fatty liver at baseline who underwent a second ultrasonography, and participants who had fatty liver at baseline but not at the second visit were considered to have had improvement of fatty liver. Remission of type-2 diabetes was defined as a fasting plasma glucose level below 126 mg/dL and an HbA1c level below 6.5% for more than 6 months without anti-diabetic drugs. Odds ratios (ORs) of remission of type-2 diabetes were estimated using logistic-regression models. RESULTS: A lower proportion of patients who had fatty liver detected by ultrasonography at baseline (8.7%, 167/1910) had remission of type-2 diabetes during the follow-up period than patients without fatty liver (13.1%, 86/657). Fatty liver at baseline was associated with a lower odds of remission of type-2 diabetes (multivariable-adjusted OR, 0.51; 95% CI, 0.37-0.72). A higher proportion of patients who had improvement of fatty liver had remission of type-2 diabetes (21.1%, 32/152) than patients with no improvement of fatty liver (7.7%, 129/1681). Improvement of fatty liver was associated with a higher odds of remission of type-2 diabetes (multivariable-adjusted OR, 3.08; 95% CI, 1.94-4.88). CONCLUSIONS: Over a follow-up period of approximate 2 years, remission of type-2 diabetes was less common in people with fatty liver detected by ultrasonography, and improvement of fatty liver was independently associated with type-2 diabetes remission.

The risk trajectory of different cardiovascular morbidities associated with chronic kidney disease among patients with newly diagnosed diabetes mellitus: a propensity score-matched cohort analysis.

BACKGROUND: Chronic kidney disease (CKD) introduces an increased cardiovascular risk among patients with diabetes mellitus (DM). The risk and tempo of cardiovascular diseases may differ depending upon their type. Whether CKD differentially influences the risk of developing each cardiovascular morbidity in patients with newly diagnosed DM remains unexplored. METHODS: We identified patients with incident DM from the Longitudinal Cohort of Diabetes Patients (LCDP) cohort (n = 429,616), and uncovered those developing CKD after DM and their propensity score-matched counterparts without. After follow-up, we examined the cardiovascular morbidity-free rates of patients with and without CKD after DM, followed by Cox proportional hazard regression analyses. We further evaluated the cumulative risk of developing each outcome consecutively during the study period. RESULTS: From LCDP, we identified 55,961 diabetic patients with CKD and matched controls without CKD. After 4.2 years, patients with incident DM and CKD afterward had a significantly higher risk of mortality (hazard ratio [HR] 1.1, 95% confidence interval [CI] 1.06-1.14), heart failure (HF) (HR 1.282, 95% CI 1.19-1.38), acute myocardial infarction (AMI) (HR 1.16, 95% CI 1.04-1.3), and peripheral vascular disease (PVD) (HR 1.277, 95% CI 1.08-1.52) compared to those without CKD. The CKD-associated risk of mortality, HF and AMI became significant soon after DM occurred and remained significant throughout follow-up, while the risk of PVD conferred by CKD did not emerge until 4 years later. The CKD-associated risk of ischemic, hemorrhagic stroke and atrial fibrillation remained insignificant. CONCLUSIONS: The cardiovascular risk profile among incident DM patients differs depending on disease type. These findings can facilitate the selection of an optimal strategy for early cardiovascular care for newly diagnosed diabetic patients.

Clinicopathological and molecular characterisation of USP6-rearranged soft tissue neoplasms: the evidence of genetic relatedness indicates an expanding family with variable bone-forming capacity.

AIMS: USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST). METHODS AND RESULTS: Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs> 50 mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC. CONCLUSION: MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS.

Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis.

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1ß (IL-1ß)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1ß/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.

Frailty is associated with a higher risk of developing delirium and cognitive impairment among patients with diabetic kidney disease: A longitudinal population-based cohort study.

AIMS: Delirium, a form of acute brain failure, exhibits a high incidence among older adults. Recent studies have implicated frailty as an under-recognized complication of diabetes mellitus. Whether the presence of frailty increases the risk of delirium/cognitive impairment among patients with diabetic kidney disease (DKD) remains unclear. METHODS: From the longitudinal cohort of diabetes patients (LCDP) (n = 840,000) in Taiwan, we identified adults with DKD, dividing them into those without and with different severities of frailty based on a modified FRAIL scale. Cox proportional hazard regression was utilized to examine the frailty-associated risk of delirium/cognitive impairment, identified using approaches validated by others. RESULTS: Totally 149,145 patients with DKD (mean 61.0 years, 44.2% female) were identified, among whom 31.0%, 51.7%, 16.0% and 1.3% did not have or had 1, 2 and >2 FRAIL items at baseline. After 3.68 years, 6613 (4.4%) developed episodes of delirium/cognitive impairment. After accounting for demographic/lifestyle factors, co-morbidities, medications and interventions, patients with DKD and 1, 2 and >2 FRAIL items had a progressively higher risk of developing delirium/cognitive impairment than those without (for those with 1, 2 and >2 items, hazard ratio 1.18, 1.26 and 1.30, 95% confidence interval 1.08-1.28, 1.14-1.39 and 1.10-1.55, respectively). For every FRAIL item increase, the associated risk rose by 9%. CONCLUSIONS: Frailty significantly increased the risk of delirium/cognitive impairment among patients with DKD. Frailty screening in these patients may assist in delirium risk stratification.