Gene expression in the hypothalamic-pituitary-thyroid axis in Seriola rivoliana early larvae development at different temperatures.

We analyzed the expression of genes involved in the hypothalamic-pituitary-thyroid axis (HPT-axis) in the longfin yellowtail Seriola rivoliana early larva, including temperature effects (22, 26 and 28 °C) and days of development (day one, day two, and day six after hatching). We aimed to determine if egg and larval incubation at different temperatures could disrupt this critical endocrine axis, which, in an aquaculture context, it could provoke mortality during early metamorphosis. There was a significant interaction between temperature and developmental timing on the relative expression of thyrotropin releasing hormone (trh). Larvae at 22 °C was the longest and increased more trh expression than larvae at higher temperatures. Interestingly, thyrotropin stimulating hormone (tsh) was highly expressed after hatching. Subsequently, it was downregulated at any temperature at least until day four, suggesting a temporal inhibition of the HPT axis. Therefore, we suggest that tsh-binding (tshr) to follicles should have occurred from hatching, creating a further "cascade effect" of upregulation of larval thyroglobulin (tg) from day two in a temperature-dependent manner. Consequently, new thyroid hormones should have been produced after yolk sac absorption. The above may indicate a narrow window of larval survival, where the larval transition from endogenous to exogenous feeding would depend on the correct timing to synthesize tg. Temperature significantly affected the expressions of deiodinase 1 (dio1-downregulated) and deiodinase 2 (dio2-upregulated) after hatching. The expressions of thyroid receptors alpha (trα) and beta (trß) remained constant after hatching without significant effects of temperature and days of development. Then, the differential expression on day six showed that all HPT-axis transcripts increased their expressions as larvae developed, which suggested a functional HPT. Finally, there was no evidence that any temperature would disrupt the endocrine's larval axis, which indicated that the longfin yellowtail has a wide temperature adaption. Nevertheless, based on tg upregulation, we suggest that larvae should be maintained around 25-26 °C after hatching for a better chance of survival and development.

Racial Disparities in Patients with Metastatic Tumors of the Spine: A Systematic Review.

IMPORTANCE: Disparities in access and delivery of care have been shown to disproportionately affect certain racial groups. Studies have been conducted to assess these disparities within the spinal metastasis population, but the extent of their effects in the setting of other socioeconomic measures remains unclear. OBJECTIVE: The purpose of this study was to perform a systematic review to understand the effect of racial disparities on outcomes in patients with metastatic spine disease. EVIDENCE REVIEW: The PRISMA guidelines were followed, where a comprehensive online search was performed using Pubmed, Medline, Web of Science, Cochrane, Embase, and Science Direct using MeSH terms related to metastatic spine tumor surgery and racial disparities up to February 2023. Two independent reviewers screened and analyzed articles to include studies assessing the following primary outcomes: clinical presentation, treatment type, postoperative complications, readmission, reoperation, survival and/or mortality, length of hospital stay, discharge disposition, and advance care planning. FINDINGS: A total of 13 studies were included in final analysis; 12 were retrospective cohort studies (Level of evidence III) and 1 was a prospective study (Level of evidence II). Postoperative complications were the most studied outcome in 46% of studies (6 of 13), followed by survival in 31% (4 of 13), and treatment type also in 31% (4 of 13). Overall, race was found to be significantly associated with at least one evaluated outcome in 69% of studies (9 of 13). Racial disparities were found in the incidence of cord compression, non-routine discharge, and treatment type in patients with metastatic spine disease. No differences were found on rates of post-operative ambulation, advance care planning, readmission, or survival; inconsistent results were seen for postoperative complications and length of stay. Nine studies (69%) included at least one other measure of socioeconomic status in multivariate analysis, with the two most common being insurance type and income. CONCLUSIONS AND RELEVANCE: Although some studies suggest race to be associated with presenting characteristics, treatment type and outcome of patients with spinal metastases, there was significant variability in the inclusion of measures of socioeconomic status in study analyses. As such, the association between race and outcomes in oncologic spine surgery remains unclear.

Development of a natural language processing algorithm for the detection of spinal metastasis based on magnetic resonance imaging reports.

Background: Metastasis to the spinal column is a common complication of malignancy, potentially causing pain and neurologic injury. An automated system to identify and refer patients with spinal metastases can help overcome barriers to timely treatment. We describe the training, optimization and validation of a natural language processing algorithm to identify the presence of vertebral metastasis and metastatic epidural cord compression (MECC) from radiology reports of spinal MRIs. Methods: Reports from patients with spine MRI studies performed between January 1, 2008 and April 14, 2019 were reviewed by a team of radiologists to assess for the presence of cancer and generate a labeled dataset for model training. Using regular expression, impression sections were extracted from the reports and converted to all lower-case letters with all nonalphabetic characters removed. The reports were then tokenized and vectorized using the doc2vec algorithm. These were then used to train a neural network to predict the likelihood of spinal tumor or MECC. For each report, the model provided a number from 0 to 1 corresponding to its impression. We then obtained 111 MRI reports from outside the test set, 92 manually labeled negative and 19 with MECC to test the model's performance. Results: About 37,579 radiology reports were reviewed. About 36,676 were labeled negative, and 903 with MECC. We chose a cutoff of 0.02 as a positive result to optimize for a low false negative rate. At this threshold we found a 100% sensitivity rate with a low false positive rate of 2.2%. Conclusions: The NLP model described predicts the presence of spinal tumor and MECC in spine MRI reports with high accuracy. We plan to implement the algorithm into our EMR to allow for faster referral of these patients to appropriate specialists, allowing for reduced morbidity and increased survival.

Nonquantitative CT scan Hounsfield unit as a determinant of cervical spine bone density.

OBJECTIVE: Hounsfield unit (HU) values measured using CT have been increasingly recognized to stand as a reliable corollary to dual-energy x-ray absorptiometry (DEXA) scores in evaluating bone mineral density. The authors examined the correlation between cervical HU values and DEXA T- and Z-scores and determined novel cervical HU thresholds for determining bone quality classification. METHODS: One hundred patients who underwent both cervical spine CT and DEXA, 85 patients who underwent both lumbar CT and DEXA, and 128 patients who underwent cervical and lumbar CT within 24 months at a single institution were included in this retrospective review. Two independent reviewers collected HU values from 3 cervical vertebral levels (C4-6) and 4 lumbar vertebral levels (L1-4), and the averaged values were used. Pearson's correlation coefficient analysis was performed to compare the association of cervical HU values with lumbar HU values and T- and Z-scores. The mean cervical HU values for each DEXA classification were calculated and compared. Receiver operating characteristic (ROC) curves were created to determine the threshold and its sensitivity and specificity for diagnosis. RESULTS: Cervical (C4-6) HU values and average, lumbar, and femoral T- and Z-scores had significant correlations (0.436 > r > 0.274, all p < 0.01). A strong positive correlation between cervical and lumbar HU values was found (r = 0.79, p < 0.01). The average cervical HU value of healthy patients was 361.2 (95% CI 337.1-385.3); of osteopenic patients, 312.1 (95% CI 290.3-333.8); and of osteoporotic patients, 288.4 (95% CI 262.6-314.3). There was a significant difference between the cervical HU values of healthy and osteopenic patients (p = 0.0134) and between those of healthy and osteoporotic patients (p = 0.0304). The cervical HU value of 340.98 was 73.5% specific and 57.9% sensitive for diagnosing osteopenia with an area under the ROC (AUROC) curve of 0.655. The cervical HU value of 326.5 was 88.9% specific and 63.2% sensitive for diagnosing osteoporosis with an AUROC curve of 0.749. CONCLUSIONS: This is the second large-scale study and first with a patient population from the United States to show that HU values obtained using cervical CT were significantly correlated with bone quality based on DEXA T- and Z-scores and to establish a cervical HU threshold for determining bone quality classification. These results show that cervical HU values can and should be used to predict poor bone quality in surgical cervical spine patients.

Predictors of Clavien-Dindo Grade III-IV or Grade V Complications after Metastatic Spinal Tumor Surgery: An Analysis of Sociodemographic, Socioeconomic, Clinical, Oncologic, and Operative Parameters.

The rate of major complications and 30-day mortality after surgery for metastatic spinal tumors is relatively high. While most studies have focused on baseline comorbid conditions and operative parameters as risk factors, there is limited data on the influence of other parameters such as sociodemographic or socioeconomic data on outcomes. We retrospectively analyzed data from 165 patients who underwent surgery for spinal metastases between 2012-2023. The primary outcome was development of major complications (i.e., Clavien-Dindo Grade III-IV complications), and the secondary outcome was 30-day mortality (i.e., Clavien-Dindo Grade V complications). An exploratory data analysis that included sociodemographic, socioeconomic, clinical, oncologic, and operative parameters was performed. Following multivariable analysis, independent predictors of Clavien-Dindo Grade III-IV complications were Frankel Grade A-C, lower modified Bauer score, and lower Prognostic Nutritional Index. Independent predictors of Clavien-Dindo Grade V complications) were lung primary cancer, lower modified Bauer score, lower Prognostic Nutritional Index, and use of internal fixation. No sociodemographic or socioeconomic factor was associated with either outcome. Sociodemographic and socioeconomic factors did not impact short-term surgical outcomes for metastatic spinal tumor patients in this study. Optimization of modifiable factors like nutritional status may be more important in improving outcomes in this complex patient population.

Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis. METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed. RESULTS: Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected. CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

Association between different diet quality scores and depression risk: the REGICOR population-based cohort study.

BACKGROUND: Our aim was to determine the association between diet quality and depression incidence in the population-based REGICOR cohort study, Catalonia, Spain. METHODS: Prospective observational study using participants' baseline (2003-2006), follow-up (2007-2013) and clinical records data. Five diet quality scores were derived from a food frequency questionnaire (FFQ) at baseline: the relative Mediterranean Diet Score (rMED), the Modified Mediterranean Diet Score (ModMDS), a Dietary Approaches to Stop Hypertension (DASH) score, a Healthful Plant-based Diet Index (HPDI) and the World Health Organization Healthy Diet Indicator (WHO-HDI). Participants using pharmacological antidepressant treatment were excluded as a proxy for presence of depression at baseline. At follow-up, the Patient Health Questionnaire (PHQ-9) was applied to assess depressive symptoms (≥ 10 defining depressive disorder). A secondary outcome was depression diagnosis assessed through clinical records. Logistic regression and Cox proportional hazards models were used. RESULTS: Main analysis included 3046 adults (50.3% women) with a mean age of 54.7 (SD = 11.6) years. After 6-years follow-up, 184 (6.04%) cases of depressive disorder were identified. There was 16% lower odds of depressive disorder per 1SD increase of rMED (OR = 0.84; 95%CI = 0.71-0.98). Secondary outcome analysis (n = 4789) identified 261 (5.45%) incident cases of clinical depression diagnosis over 12 years follow-up, and 19% lower risk of clinical depression was observed with the WHO-HDI (HR = 0.81; 95%CI = 0.70-0.93). Adjusting for BMI did not attenuate the findings. CONCLUSIONS: A significant inverse association between diet quality and depression incidence was found in this population-based cohort study, independent of sociodemographic, health and lifestyle. Adherence to a healthy diet could be a complementary intervention for the prevention of depression.

Prognostic impact of tumor location and gene expression profile in sporadic desmoid tumor.

PURPOSE: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed. METHOD: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation. RESULTS: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations. CONCLUSION: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/ß-catenin, TGFß, IFN, and TNF pathways.

Heterocycles as supramolecular handles for crystal engineering: a case study with 7-(diethylamino)coumarin derivatives.

In this study, we present the synthesis and detailed solid-state structural characterization of a Schiff-base-bridged derivative of 7-(diethylamino)coumarin (7-DAC), a molecular block displaying repetitive aggregation modes in the solid state despite being attached to broadly different molecular frameworks. To map the supramolecular habits of this unconventional moiety, we carry out a comparative analysis of the crystal packing in a curated dataset of 50 molecules decorated with the 7-DAC group, retrieved from the literature. We uncover that self-recognition of the 7-DAC moiety has two main components: a set of directional C-H⋯O interactions between neighboring coumarins, and antiparallel dipole-dipole interactions, taking the form of distinct π-stacking modes. The pendant 7-diethylamino group is key to the behavior of 7-DAC, favoring its solubilization through its conformational flexibility in solution, while in the crystalline matrix, it acts as a structural spacer that favors π-stacking interactions. Our findings present a comprehensive analysis of the preferential arrangements of the 7-DAC fragment in various (supra)molecular scenarios, confirming that it is (i) a mobile but mostly planar group, (ii) a group prone to antiparallel aggregation, and (iii) up to 90% likely to pack via π-stacking supported by hydrogen-bonding interactions. These findings enrich the palette of supramolecular motifs available for the bottom-up design of organic materials and their programmed construction.

Dirofilaria immitis and Dirofilaria striata (Spirurida: Onchocercidae) detected in wild carnivores from Texas, United States.

Dirofilaria immitis and Dirofilaria striata (Spirurida: Onchocercidae) are epidemiologically important filarial nematodes detected in wild carnivores sympatric to domestic animals and humans. In this study we surveyed for Dirofilaria species among previous studies archived blood samples (n = 202) of wild carnivores sourced across Texas between the years of 2014-2016 and 2020 to 2023. In total, 117 coyotes (Canis latrans), 67 raccoons (Procyon lotor), 12 gray foxes (Urocyon cinereoargenteus), five bobcats (Lynx rufus), and one striped skunk (Mephitis mephitis) were tested through the amplification of the partial cytochrome oxidase c subunit 1 (COI) gene followed by sequencing. Dirofilaria immitis was detected in 11.39% (95% CI = 7.71-16.51) of the samples (21 coyotes and two raccoons), while D. striata was detected in a single bobcat. Dirofilaria immitis sequences had 99.85%-100% (99.92% ± 0.08) similarity with other D. immitis sequences in GenBank. The sequence of D. striata from the bobcat was 100% similar to the single COI sequence available in GenBank. Data from this study reinforce the role of coyotes as a wild reservoir for D. immitis and suggest that raccoons may also play a role in the epidemiology of this parasite. This study additionally provides molecular data on D. striata, an understudied filarioid of felids.

Area Socioeconomic Status is Associated with Refusal of Recommended Surgery in Patients with Metastatic Bone and Joint Disease.

BACKGROUND: This study sought to identify associations between the Yost Index, a geocoded area neighborhood socioeconomic status (nSES) score, and race/ethnicity with patient refusal of recommended surgery for metastatic bone disease. METHODS: Patients with metastatic bone disease were extracted from the Surveillance, Epidemiology, and End Results database. The Yost Index was geocoded using factor analysis and categorized into quintiles using census tract-level American Community Service (ACS) 5-year estimates and seven nSES measures. Multivariable logistic regression models calculated odds ratios (ORs) of refusal of recommended surgery and 95% confidence intervals (CIs), adjusting for clinical covariates. RESULTS: A total of 138,257 patients were included, of which 14,943 (10.8%) were recommended for surgical resection. Patients in the lowest nSES quintile had 57% higher odds of refusing surgical treatment than those in the highest quintile (aOR = 1.57, 95% CI 1.30-1.91, p < 0.001). Patients in the lowest nSES quintile also had a 31.2% higher age-adjusted incidence rate of not being recommended for surgery compared with those in the highest quintile (186.4 vs. 142.1 per 1 million, p < 0.001). Black patients had 34% higher odds of refusing treatment compared with White patients (aOR = 1.34, 95% CI 1.14-1.58, p = 0.003). Advanced age, unmarried status, and patients with aggressive cancer subtypes were associated with higher odds of refusing surgery (p < 0.001). CONCLUSIONS: nSES and race/ethnicity are independent predictors of a patient refusing surgery for metastatic cancer to bone, even after adjusting for various clinical covariates. Effective strategies for addressing these inequalities and improving the access and quality of care of patients with a lower nSES and minority backgrounds are needed.

Isolation and Visualization of Plant Stress Granule-Associated Components via On-Beads Digestion and Co-localization Analysis.

Stress granules (SGs) are conserved cytoplasmic biomolecular condensates mainly formed by proteins and RNA molecules assembled by liquid-liquid phase separation. Isolation of SGs components has been a major challenge in the field due to the dynamic and transient nature of stress granule shells. Here, we describe the methodology for the isolation and visualization of SGs proteins from Arabidopsis thaliana plants using a scaffold component as the target. The protocol consists of the first immunoprecipitation of GFP-tagged scaffold protein, followed by an on-beads enzymatic digestion and previous mass spectrometry identification. Finally, the localization of selected SGs candidates is visualized in Nicotiana benthamiana mesophyll protoplasts.

Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men.

BACKGROUND: An altered gut microbiome characterized by reduced abundance of butyrate producing bacteria and reduced gene richness is associated with type 2 diabetes (T2D). An important complication of T2D is increased risk of cognitive impairment and dementia. The biguanide metformin is a commonly prescribed medication for the control of T2D and metformin treatment has been associated with a significant reduction in the risk of dementia and improved cognition, particularly in people with T2D. AIM: To investigate the associations of metformin use with cognition exploring potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. METHODS: We explored two independent cohorts: an observational study (Aging Imageomics) and a phase IV, randomized, double-blind, parallel-group, randomized pilot study (MEIFLO). From the two studies, we analyzed four study groups: (1) individuals with no documented medical history or medical treatment (n = 172); (2) people with long-term T2D on metformin monotherapy (n = 134); (3) people with long-term T2D treated with oral hypoglycemic agents other than metformin (n = 45); (4) a newly diagnosed T2D subjects on metformin monotherapy (n = 22). Analyses were also performed stratifying by sex. RESULTS: Several bacterial species belonging to the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated with metformin treatment, while bacterial species belonging to the Firmicutes phylum (Romboutsia timonensis, Romboutsia ilealis) were negatively associated. Due to the consistent increase in A. muciniphila and decrease in R.ilealis in people with T2D subjects treated with metformin, we investigated the association between this ratio and cognition. In the entire cohort of metformin-treated T2D subjects, the A.muciniphila/R.ilealis ratio was not significantly associated with cognitive test scores. However, after stratifying by sex, the A.muciniphila/R. ilealis ratio was significantly and positively associated with higher memory scores and improved memory in men. Metformin treatment was associated with an enrichment of microbial pathways involved in the TCA cycle, and butanoate, arginine, and proline metabolism in both cohorts. The bacterial genes involved in arginine metabolism, especially in production of glutamate (astA, astB, astC, astD, astE, putA), were enriched following metformin intake. In agreement, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in the metabolism of glutamate. CONCLUSIONS: The beneficial effects of metformin may be mediated by changes in the composition of the gut microbiota and microbial-host-derived co-metabolites.

Multidisciplinary surgical considerations for en bloc resection of sacral chordoma: review of recent advances and a contemporary single-center series.

OBJECTIVE: Contemporary management of sacral chordomas requires maximizing the potential for recurrence-free and overall survival while minimizing treatment morbidity. En bloc resection can be performed at various levels of the sacrum, with tumor location and volume ultimately dictating the necessary extent of resection and subsequent tissue reconstruction. Because tumor resection involving the upper sacrum may be quite destabilizing, other pertinent considerations relate to instrumentation and subsequent tissue reconstruction. The primary aim of this study was to survey the surgical approaches used for managing primary sacral chordoma according to location of lumbosacral spine involvement, including a narrative review of the literature and examination of the authors' institutional case series. METHODS: The authors performed a narrative review of pertinent literature regarding reconstruction and complication avoidance techniques following en bloc resection of primary sacral tumors, supplemented by a contemporary series of 11 cases from their cohort. Relevant surgical anatomy, advances in instrumentation and reconstruction techniques, intraoperative imaging and navigation, soft-tissue reconstruction, and wound complication avoidance are also discussed. RESULTS: The review of the literature identified several surgical approaches used for management of primary sacral chordoma localized to low sacral levels (mid-S2 and below), high sacral levels (involving upper S2 and above), and high sacral levels with lumbar involvement. In the contemporary case series, the majority of cases (8/11) presented as low sacral tumors that did not require instrumentation. A minority required more extensive instrumentation and reconstruction, with 2 tumors involving upper S2 and/or S1 levels and 1 tumor extending into the lower lumbar spine. En bloc resection was successfully achieved in 10 of 11 cases, with a colostomy required in 2 cases due to rectal involvement. All 11 cases underwent musculocutaneous flap wound closure by plastic surgery, with none experiencing wound complications requiring revision. CONCLUSIONS: The modern management of sacral chordoma involves a multidisciplinary team of surgeons and intraoperative technologies to minimize surgical morbidity while optimizing oncological outcomes through en bloc resection. Most cases present with lower sacral tumors not requiring instrumentation, but stabilizing instrumentation and lumbosacral reconstruction are often required in upper sacral and lumbosacral cases. Among efforts to minimize wound-related complications, musculocutaneous flap closure stands out as an evidence-based measure that may mitigate risk.

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

Cardio-ankle vascular index for predicting cardiovascular morbimortality and determinants for its progression in the prospective advanced approach to arterial stiffness (TRIPLE-A-Stiffness) study.

BACKGROUND: The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression. METHODS: TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81-4.69) years. FINDINGS: Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03-1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10-1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542-0.654) and 8.30 (c-index 0.565; 0.512-0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI. INTERPRETATION: The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments. FUNDING: International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.

Intraepithelial Lymphogram in the Diagnosis of Celiac Disease in Adult Patients: A Validation Cohort.

BACKGROUND: Celiac disease is a gluten-related pathology, highly prevalent and heterogeneous in its clinical presentation, which leads to delays in diagnosis and misdiagnosis. The analysis of duodenal intraepithelial lymphocytes (IELs) by flow cytometry (lymphogram) is emerging as a discriminative tool in the diagnosis of various forms of celiac disease (CD). AIMS: The aim of this study was to validate IEL lymphogram performance in the largest adult series to our knowledge, in support of its use as a diagnostic tool and as a biomarker of the dynamic celiac process. METHODS: This was a retrospective study including 768 adult patients (217 with active CD, 195 on a gluten-free diet, 15 potential CD patients, and 411 non-celiac controls). The IEL subset cut-off values were established to calculate the diagnostic accuracy of the lymphogram. RESULTS: A complete celiac lymphogram profile (≥14% increase in T cell receptor [TCR]γδ IELs and simultaneous ≤4% decrease in surface-negative CD3 [sCD3-] IELs) was strongly associated with active and potential forms in over 80% of the confirmed patients with CD, whereas the remaining patients with CD had partial lymphogram profiles (≥14% increase in TCRγδ or ≤4% decrease in sCD3- IELs), with lower diagnostic certainty. None of these patients had a non-celiac lymphogram. Quantifying the TCRγδ versus sCD3- imbalance as a ratio (≥5) is a discriminative index to discard or suspect CD at diagnosis. CONCLUSIONS: We have validated the IEL lymphogram's diagnostic efficiency (79% sensitivity, 98% specificity), with an LR+ accuracy of 36.2. As expected, the increase in TCRγδ IELs is a reliable marker for celiac enteropathy, while changes in sCD3- IEL levels throughout the dynamic CD process are useful biomarkers of mucosal lesions.

Chemical Composition and Acaricidal Activity of Essential Oil of Lavandula dentata L. on Engorged Females of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).

PURPOSE: Rhipicephalus (Boophilus) microplus is one the most significant ectoparasite in cattle farming in tropical and subtropical regions, causing problems to livestock health worldwide. The control of this ectoparasite primarily relies on the use of synthetic acaricides. However, the emergence of acaricide resistance has stimulated the search for new control alternatives, including phytocompounds with acaricidal and insecticidal potential. The aim of this study was to evaluate the acaricidal potential of Lavandula dentata essential oil against the engorged females of R. (B.) microplus. METHODS: Engorged females were obtained from infested bovines in dairy farms in Pernambuco, Brazil. L. dentata essential oil was extracted, and adult immersion test assays were performed using the following oil concentrations: 0.2%, 0.4%, 0.6%, 0.8%, and 1%. RESULTS: L. dentata essential oil at a concentration of 1% was lethal to all engorged females, and concentrations of 0.6% and 0.8% caused mortality of 98.6% and 99.1%, respectively. These concentrations disrupted the reproductive capacity of engorged females, reducing oviposition by more than 90% and preventing egg hatching by over 87%. CONCLUSION: The data revealed that L. dentata essential oil possesses effective pharmacological properties against R. (B.) microplus and could be used for tick control following in vivo evaluation, thus contributing to mitigating the negative impacts of synthetic acaricide use.

Disparities in postoperative complications and perioperative events based on insurance status following elective spine surgery: A systematic review and meta-analysis.

Background: Increasing evidence demonstrates disparities among patients with differing insurance statuses in the field of spine surgery. However, no pooled analyses have performed a robust review characterizing differences in postoperative outcomes among patients with varying insurance types. Methods: A comprehensive literature search of the PUBMED, MEDLINE(R), ERIC, and EMBASE was performed for studies comparing postoperative outcomes in patients with private insurance versus government insurance. Pooled incidence rates and odds ratios were calculated for each outcome and meta-analyses were conducted for 3 perioperative events and 2 types of complications. In addition to pooled analysis, sub-analyses were performed for each outcome in specific government payer statuses. Results: Thirty-eight studies (5,018,165 total patients) were included. Compared with patients with private insurance, patients with government insurance experienced greater risk of 90-day re-admission (OR 1.84, p<.0001), non-routine discharge (OR 4.40, p<.0001), extended LOS (OR 1.82, p<.0001), any postoperative complication (OR 1.61, p<.0001), and any medical complication (OR 1.93, p<.0001). These differences persisted across outcomes in sub-analyses comparing Medicare or Medicaid to private insurance. Similarly, across all examined outcomes, Medicare patients had a higher risk of experiencing an adverse event compared with non-Medicare patients. Compared with Medicaid patients, Medicare patients were only more likely to experience non-routine discharge (OR 2.68, p=.0007). Conclusions: Patients with government insurance experience greater likelihood of morbidity across several perioperative outcomes. Additionally, Medicare patients fare worse than non-Medicare patients across outcomes, potentially due to age-based discrimination. Based on these results, it is clear that directed measures should be taken to ensure that underinsured patients receive equal access to resources and quality care.

STAT6-targeting antisense oligonucleotides against solitary fibrous tumor.

Solitary fibrous tumor (SFT) is a rare, non-hereditary soft tissue sarcoma thought to originate from fibroblastic mesenchymal stem cells. The etiology of SFT is thought to be due to an environmental intrachromosomal gene fusion between NGFI-A-binding protein 2 (NAB2) and signal transducer and activator protein 6 (STAT6) genes on chromosome 12, wherein the activation domain of STAT6 is fused with the DNA-binding domain of NAB2 resulting in the oncogenesis of SFT. All NAB2-STAT6 fusion variations discovered in SFTs contain the C-terminal of STAT6 transcript, and thus can serve as target site for antisense oligonucleotides (ASOs)-based therapies. Indeed, our in vitro studies show the STAT6 3' untranslated region (UTR)-targeting ASO (ASO 993523) was able to reduce expression of NAB2-STAT6 fusion transcripts in multiple SFT cell models with high efficiency (half-maximal inhibitory concentration: 116-300 nM). Encouragingly, in vivo treatment of SFT patient-derived xenograft mouse models with ASO 993523 resulted in acceptable tolerability profiles, reduced expression of NAB2-STAT6 fusion transcripts in xenograft tissues (21.9%), and, importantly, reduced tumor growth (32.4% decrease in tumor volume compared with the untreated control). Taken together, our study established ASO 993523 as a potential agent for the treatment of SFTs.