Normal values of myocardial blood flow measured with dynamic myocardial computed tomography perfusion.

AIMS: Dynamic myocardial computed tomography (CT) perfusion (DM-CTP) can, in combination with coronary CT angiography (CCTA), provide anatomical and functional evaluation of coronary artery disease (CAD). However, normal values of myocardial blood flow (MBF) are needed to identify impaired myocardial blood supply in patients with suspected CAD. We aimed to establish normal values for MBF measured using DM-CTP, to assess the effects of age and sex, and to assess regional distribution of MBF. METHODS AND RESULTS: A total of 82 healthy individuals (46 women) aged 45-78 years with normal coronary arteries by CCTA underwent either rest and adenosine stress DM-CTP (n = 30) or adenosine-induced stress DM-CTP only (n = 52). Global and segmental MBF were assessed. Global MBF at rest and during stress were 0.93 ± 0.42 and 3.58 ± 1.14 mL/min/g, respectively. MBF was not different between the sexes (P = 0.88 at rest and P = 0.61 during stress), and no correlation was observed between MBF and age (P = 0.08 at rest and P = 0.82 during stress). Among the 16 myocardial segments, significant intersegmental differences were found (P < 0.01), which was not related to age, sex, or coronary dominance. CONCLUSION: MBF assessed by DM-CTP in healthy individuals with normal coronary arteries displays significant intersegmental heterogeneity which does not seem to be affected by age, sex, or coronary dominance. Normal values of MBF may be helpful in the clinical evaluation of suspected myocardial ischaemia using DM-CTP.

System stability and signal enhancement with analyte protectants: Gas chromatography analysis of oxygenated-polycyclic aromatic hydrocarbons.

Matrix effects can affect detection limits, precision, and accuracy and lead to signal enhancement or suppression effects in gas chromatography analysis. Analyte protectants, such as shikimic acid and gluconolactone, can imitate the effect of matrix components and reduce the differences in matrix effect between samples. This study aimed to investigate the ability of analyte protectants to enhance gas chromatography detector signals of different oxygenated-polycyclic aromatic hydrocarbons. Addition of 100 µg L-1 shikimic acid and 200 µg L-1 gluconolactone effectively enhanced detector response of the investigated target compounds. Addition of a higher content of analyte protectants did not result in any further enhancement. It was found that between four and eleven consecutive injections of a standard solution with analyte protectants were required to obtain a stable compound response. The long-term signal stability was then maintained with subsequent injections, though an overall negative drift of the system was observed over the sequence of 200 investigated injections. Analysis of the actual sample matrix instead of standards in pure solvent, as presented in this study, could also be a way to minimize the required number of injections. Shikimic acid and gluconolactone were first and foremost able to enhance signals of oxygenated-polycyclic aromatic hydrocarbons with similar functional groups (hydroxyl) in their molecular structure. It can be relevant to consider alternative analyte protectants with different functional groups according to the type of target compounds investigated.

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis.

Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.

Catchment area, fate, and environmental risks investigation of micropollutants in Danish wastewater.

This study aimed to investigate the spatial distribution of micropollutants in wastewater related to catchment area, and their environmental risks and fate. About 24-h flow proportional effluent (n = 26) wastewater samples were collected from eight WWTPs across Denmark. From five of these WWTPs corresponding influent samples (n = 20) were collected. Samples were enriched by multi-layer solid phase and analysed by liquid chromatography-high-resolution mass spectrometry and comprehensive two-dimensional gas chromatography with high-resolution mass spectrometry detection. We detected and quantified 79 micropollutants from a list of 291 micropollutants in at least one influent or effluent wastewater sample. From this we found that 54 micropollutants decreased in concentrations during wastewater treatment, while O-desmethylvenlafaxine, carbamazepine, amitriptyline, benzothiazole, terbutryn, and citalopram increased in concentrations through the WWTP.The toxicity of effluent wastewater samples was assessed by EC50 using Raphidocelis subcapitata (R. subcapitata) and LC50 using the crustacean Daphnia magna (D. Magna), for which six micropollutants were detected above the predicted no-effect concentration. Our study demonstrates that catchment area influences the micropollutant composition of wastewater. Out of 19 pharmaceuticals, the measured concentration in influent wastewater was predicted within a factor of 10 from sale numbers and human excretion, which demonstrates the strong influence of catchment area on micropollutant composition.

Supercritical Fluid Chromatography Coupled to High-Resolution Mass Spectrometry Reveals Persistent Mobile Organic Compounds with Unknown Toxicity in Wastewater Effluents.

Broad screening approaches for monitoring wastewater are normally based on reversed-phase liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS). This method is not sufficient for the very polar micropollutants, neglected in the past due to a lack of suitable analytical methods. In this study, we used supercritical fluid chromatography (SFC) to detect very polar and yet-undetected micropollutants in wastewater effluents. We tentatively identified 85 compounds, whereas 18 have only rarely been detected and 11 have not previously been detected in wastewater effluents such as 17α-hydroxypregnenolone, a likely transformation product (TP) of steroids, and 1H-indole-3-carboxamide, a likely TP from new synthetic cannabinoids. Suspect screening of 25 effluent wastewater samples from 8 wastewater treatment plants revealed several distinct potential pollution sources such as a pharmaceutical company and a golf court. The analysis of the same samples with LC-HRMS showed clearly how SFC increases the ionization efficiency for low-molecular-weight micropollutants (m/z < 300 Da) by a factor 2 to 87 times, which significantly improved the mass spectra for identifying very polar compounds. In order to assess which micropollutants might be of environmental concern, literature and toxicological databases were screened. There was a lack of available hazard and bio-activity data for regulatory-relevant in vitro and in vivo assays for >50% of the micropollutants. Especially, 70% of the data were lacking for the whole organism (in vivo) tests.

Quantification of myocardial blood flow using dynamic myocardial CT perfusion compared with 82Rb PET.

PURPOSE: Absolute measures of myocardial blood flow (MBF) obtained with dynamic myocardial CT perfusion (DM-CTP) are underestimated when compared with reference standards. This is to some extent explained by incomplete extraction of iodinated contrast agent (iCA) to the myocardial tissue. We aimed to establish an extraction function for iCA, use the function to calculate MBFCT and to compare this with MBF measured with 82Rb positron emission tomography (PET). MATERIALS AND METHODS: Healthy individuals without coronary artery disease (CAD) were examined with 82Rb PET and DM-CTP. The factors a and ß of the generalized Renkin-Crone model were estimated using a non-linear least squares model. The factors providing the best fit for the data were subsequently used to calculate MBFCT. RESULTS: Of consecutive 91 individuals examined, 79 were eligible for analysis. The factors a and ß providing the best fit of the nonlinear least-squares model to the data were a â€‹= â€‹0.614 and ߠ​= â€‹0.218 (R-squared â€‹= â€‹0.81). Conversion of the CT inflow parameter (K1) values using the derived extraction function resulted in a significant correlation between MBF measured during stress using CT and PET (P â€‹= â€‹0.039). CONCLUSION: In healthy individuals, flow estimates obtained with dynamic myocardial CT perfusion during stress were, after conversion to MBF using the extraction of iodinated CT contrast agent, correlated with absolute MBF quantified with 82Rb PET.

Chemical Modifications and Design Influence the Potency of Huntingtin Anti-Gene Oligonucleotides.

Huntington's disease is a neurodegenerative, trinucleotide repeat (TNR) disorder affecting both males and females. It is caused by an abnormal increase in the length of CAG•CTG TNR in exon 1 of the Huntingtin gene (HTT). The resultant, mutant HTT mRNA and protein cause neuronal toxicity, suggesting that reduction of their levels would constitute a promising therapeutic approach. We previously reported a novel strategy in which chemically modified oligonucleotides (ONs) directly target chromosomal DNA. These anti-gene ONs were able to downregulate both HTT mRNA and protein. In this study, various locked nucleic acid (LNA)/DNA mixmer anti-gene ONs were tested to investigate the effects of varying ON length, LNA content, and fatty acid modification on HTT expression. Altering the length did not significantly influence the ON potency, while LNA content was critical for activity. Utilization of palmitoyl-modified LNA monomers enhanced the ON activity relatively to the corresponding nonmodified LNA under serum starvation conditions. Furthermore, the number of palmitoylated LNA monomers and their positioning greatly affected ON potency. In addition, we performed RNA sequencing analysis, which showed that the anti-gene ONs affect the "immune system process, mRNA processing, and neurogenesis." Furthermore, we observed that for repeat containing genes, there is a higher tendency for antisense off-targeting. Taken together, our findings provide an optimized design of anti-gene ONs that could potentially be developed as DNA-targeting therapeutics for this class of TNR-related diseases.

Technical Considerations for Dynamic Myocardial Computed Tomography Perfusion as Part of a Comprehensive Evaluation of Coronary Artery Disease Using Computed Tomography.

Dynamic myocardial computed tomography perfusion (DM-CTP) has good diagnostic accuracy for identifying myocardial ischemia as compared with both invasive and noninvasive reference standards. However, DM-CTP has not yet been implemented in the routine clinical examination of patients with suspected or known coronary artery disease. An important hurdle in the clinical dissemination of the method is the development of the DM-CTP acquisition protocol and image analysis. Therefore, the aim of this article is to provide a review of critical parameters in the design and execution of DM-CTP to optimize each step of the examination and avoid common mistakes. We aim to support potential users in the successful implementation and performance of DM-CTP in daily practice. When performed appropriately, DM-CTP may support clinical decision making. In addition, when combined with coronary computed tomography angiography, it has the potential to shorten the time to diagnosis by providing immediate visualization of both coronary atherosclerosis and its functional relevance using one single modality.

[Diagnostics and treatment of organic intraorbital foreign bodies]. / Diagnostik und Therapie organischer intraorbitaler Fremdkörper.

BACKGROUND: Orbital injuries with organic foreign bodies are a clinical challenge as they can cause a variety of complications and sometimes lead to irreversible visual impairment. MATERIAL AND METHODS: We report five consecutive cases of patients with organic orbital foreign bodies who presented between 2012 and 2022. Documented parameters include age, gender, time of injury, mechanism of injury, best-corrected visual acuity (BCVA), presence of pain, restriction of motility, performed imaging, location and type of foreign body, treatment and complications. RESULTS: The mean patient age was 61.8 ± 32.3 years and the gender ratio was 4:1 (female:male). In 4 cases the injury had been reported on average 4.6 days (0/14 days min/max) previously. Best corrected visual acuity at first presentation was 0.5 ± 0.2 decimal and after a mean follow-up of 12.7 months (0.5/38 months min/max) at last presentation 0.67 ± 0.3 decimal (p = 0.2). The reason for initial presentation was pain (n = 3) and/or double vision (n = 2). All patients underwent computer tomography (CT). The diagnosis was confirmed in two cases by means of CT. In all five cases the foreign body material could be completely surgically removed, while one patient needed repeated surgery due to retained foreign body material. The organic foreign body material included wood (4) and wax (1). In two cases, a foreign body-induced infection was successfully treated with systemic antibiotics. There were no other complications. CONCLUSION: In orbital trauma a thorough wound exploration must be performed, especially if the mechanism of injury is uncertain and residual foreign bodies or a perforation injury cannot be excluded. The imaging of choice is CT, which may have to be performed again in the postoperative course.

Projection of primary and revision hip arthroplasty surgery in Denmark from 2020 to 2050.

BACKGROUND AND PURPOSE: The incidence of primary and revision total hip arthroplasty (THA) has increased over the last decades. Previous forecasts from different healthcare systems have predicted a continuous increase. We present a forecast of both primary and revision surgery from 2020 to 2050 based on 25 years data from the healthcare system in Denmark. PATIENTS AND METHODS: We retrieved data from the Danish Hip Arthroplasty Register on 198,835 primary and 29,456 revision surgeries. Historical censuses and population forecasts were retrieved from Statistics Denmark. Logistic and Gompertz regression analysis was used to forecast incidence rates (IR) and total numbers in the next 30 years. RESULTS: Our forecast predicts an increase in IR of 3-9% and an increase in total numbers of primary THA of between 12% and 19% in 2050. For revision THA the IRs have reached a plateau but total numbers are predicted to increase by 19% in 2050. CONCLUSION: Our forecast shows that both primary and revision THA will increase in total numbers in the next decades, but the IR for primary THA is near its plateau and for revision THA the plateau has already been reached. The forecast may aid in healthcare resource planning for the decades to come.

A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity.

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.

Can analyte protectants compensate wastewater matrix induced enhancement effects in gas chromatography - mass spectrometry analysis?

This study aimed to investigate the ability of analyte protectants to enhance GC-MS signals and compensate matrix effects for a range of micropollutants in pure standard, effluent, and influent wastewater samples during analysis and detection. Wastewater samples were prepared for analysis using multilayer solid phase extraction for the purpose of extracting sample components with a broad range of physical-chemical properties. The sample extracts were either spiked or not spiked with target compounds and four analyte protectants: 3-ethoxy-1,2-propanediol, D-sorbitol, gluconolactone, and shikimic acid. In this way, it was possible to evaluate the matrix effects of wastewater samples and compare the use of analyte protectants with the conventional correction method of allocating a best matching internal standard to each target compound. A relation was observed between level of wastewater treatment and matrix effects, with the largest effects observed for influent samples and the smallest effects for effluent samples. Compensation of matrix effects with analyte protectants gave comparable results with the conventional correction method of allocating a best matching internal standard to each of the 13 investigated micropollutants. The best overall compensation was observed using analyte protectants and the internal standard correction method in combination.

Patients with Pulmonary Metastases from Head and Neck Cancer Benefit from Pulmonary Metastasectomy, A Systematic Review.

Background and Objectives: The incidence of distant metastases in patients with head and neck cancer (HNC) is approximately 10%. Pulmonary metastases are the most frequent distant location, with an incidence of 70-85%. The standard treatment options are chemo-, immuno- and radiotherapy. Despite a benefit for long-term survival for patients with isolated pulmonary metastases, pulmonary metastasectomy (PM) is not the treatment of choice. Furthermore, many otorhinolaryngologists are not sufficiently familiar with the concept of PM. This work reviews the recent studies of pulmonary metastatic HNC and the results after pulmonary metastasectomy. Materials and Methods: PubMed, Medline, Embase, and the Cochrane library were checked for the case series' of patients undergoing metastasectomy with pulmonary metastases published since 1 January 2000. Results: We included the data of 15 studies of patients undergoing PM. The 5-year survival rates varied from 21% to 59%, with median survival from 10 to 77 months after PM. We could not identify one specific prognostic factor for long-term survival after surgery. However, at least most studies stated that PM should be planned if a complete (R0) resection is possible. Conclusions: PM showed reliable results and is supposedly the treatment of choice for patients with isolated pulmonary metastases. Patients not suitable for surgery may benefit from other non-surgical therapy. Every HNC patient with pulmonary metastases should be discussed in the multidisciplinary tumor board to optimize the therapy and the outcome.

Early Coronary Atherosclerosis in Women With Previous Preeclampsia.

BACKGROUND: Women with previous preeclampsia have an increased risk of coronary artery disease later in life. OBJECTIVES: This study aimed to determine the prevalence of coronary atherosclerosis in younger women with previous preeclampsia in comparison with women from the general population. METHODS: Women aged 40-55 years with previous preeclampsia were matched 1:1 on age and parity with women from the general population. Participants completed an extensive questionnaire, a clinical examination, and a coronary computed tomography angiography (CTA). The main study outcome was the prevalence of any coronary atherosclerosis on coronary CTA or a calcium score >0 in case of a nondiagnostic coronary CTA. RESULTS: A total of 1,417 women, with a mean age of 47 years, were included (708 women with previous preeclampsia and 709 control subjects from the general population). Women with previous preeclampsia were more likely to have hypertension (284 [40.1%] vs 162 [22.8%]; P < 0.001), dyslipidemia (338 [47.7%] vs 296 [41.7%]; P = 0.023), diabetes mellitus (24 [3.4%] vs 8 [1.1%]; P = 0.004), and high body mass index (27.3 ± 5.7 kg/m2 vs 25.0 ± 4.2 kg/m2; P < 0.001). Cardiac computed tomography was performed in all women. The prevalence of any coronary atherosclerosis was higher in the preeclampsia group (193 [27.4%] vs 141 [20.0%]; P = 0.001) with an OR: 1.41 (95% CI: 1.08-1.85; P = 0.012) after adjustment for age, dyslipidemia, diabetes mellitus, smoking, body mass index, menopause, and parity. CONCLUSIONS: Younger women with previous preeclampsia had a slightly higher prevalence of coronary atherosclerosis compared with age- and parity-matched women from the general population. Preeclampsia remained an independent risk factor after adjustment for traditional cardiovascular risk factors. (The CoPenHagen PREeClampsia and cardIOvascUlar diSease study [CPH-PRECIOUS]; NCT03949829).

Evaluation of Gene Expression Knock-Down by Chemically and Structurally Modified Gapmer Antisense Oligonucleotides.

We analyzed the effect of modified nucleotides within gapmer antisense oligonucleotides on RNase H mediated gene silencing. Additionally, short hairpins were introduced into antisense oligonucleotides as structural motifs, and their influence on biological and physicochemical properties of pre-structured gapmers was investigated for the first time. The results indicate that two LNA residues in specified positions of the gap flanking regions are sufficient and favorable for efficient knock-down of the ß-actin gene. Furthermore, the introduction of other modified nucleotides, i. e. glycyl-amino-LNA-T, 2'-O-propagyluridine, polyamine functionalized uridine, and UNA, in specified positions, also increases the inhibition of ß-actin expression. Importantly, the presence of hairpins within the gapmers improves their silencing properties.

Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through ß3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial.

BACKGROUND: ß3-AR (ß3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the ß3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. METHODS: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. RESULTS: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P=0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P=0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. CONCLUSIONS: Oral treatment with the ß3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: 2016-002367-34.

From data to reliable conclusions: Identification and comparison of persistent micropollutants and transformation products in 37 wastewater samples by non-target screening prioritization.

In this study, micropollutants in wastewater effluents were prioritized by monitoring the composition of influent and effluent wastewater by liquid chromatography - high-resolution mass spectrometry (LCHRMS) non-target screening (NTS) analysis. The study shows how important data pre-processing and filtering of raw data is to produce reliable NTS data for comparison of compounds between many samples (37 wastewater samples) analyzed at different times. Triplicate injections were critical for reducing the number of false-positive detections. Intensity drift corrections within and between batches analyzed months apart made peak intensities comparable across samples. Adjustment of the feature detection threshold was shown to be important, due to large intensity variations for low abundance compounds across batches. When the threshold correction cut-offs, or the filtering of relevant compounds by the occurrence frequency, were too stringent, a high number of false positive transformation products (TPs) were reported. We also showed that matrix effect correction by internal standards can over- or under-correct the intensity for unknown compounds, thus the TIC matrix effect correction was shown as an additional tool for a retention time dependent matrix effect correction. After these preprocessing and filtering steps, we identified 78 prioritized compounds, of which 36 were persistent compounds, defined as compounds with a reduction in peak intensity between influent and effluent wastewater <50%, and 13 compounds were defined as TPs because they occurred solely in the effluent samples. Some examples of persistent compounds are 1,3-diphenylguanidine, amisulpride and the human metabolites from losartan, verapamil and methadone. To our knowledge, nine of the identified TPs have not been previously described in effluent wastewater. The TPs were derived from metoprolol, fexofenadine, DEET and losartan. The screening of all identified compounds in effluent samples from eight wastewater treatment plants (WWTPs) showed that potential drugs of abuse, anti-psychotic and anti-depressant drugs were predominant in the capital city region, whereas the anti-epileptic agents and agricultural pesticides were dominant in more rural areas.

Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.

Micro-computed tomography of sandstone rocks: Raw, filtered and segmented datasets.

High-resolution computed micro-tomography is an important area of science, which correlates well with several experimental methodologies and serves as a basis for advanced computational physics studies, in which high-resolution images are used as input to different scientific simulation models. The dataset presented herein includes (raw) grayscale images obtained using the Bruker Skyscan 1272 X-Ray tomograph; filtered images acquired through contrast enhancement and noise reduction filters; and segmented images obtained by using the IsoData segmentation method. All images have a resolution of 2.25 µm (isometric voxels) and size of 10003 voxels.

Water polo-related injuries among adolescents and young adults treated at emergency departments.

OBJECTIVES: Water polo is a physically demanding contact sport involving swimming, overhead throwing, and wrestling/defending that can result in acute injuries. The objective of this study was to characterize water polo-related injuries among adolescents and young adults treated at United States (US) emergency departments (EDs). METHODS: Cases were water polo-related injuries among patients age 13-25 years reported to the National Electronic Injury Surveillance System (NEISS) during 2000-2019. The distribution of the national injury estimates was determined for selected variables. RESULTS: A total of 418 water polo-related injuries among patients age 13-25 years treated at US EDs during 2000-2019 were identified, resulting in a national estimate of 15,426 injuries. The patient was age 13-18 years in 73.5% of the injuries, 19-22 years in 20.5%, and 23-25 years in 6.0%; 62.1% of the patients were male and 37.9% female. The injury occurred at a place of recreation or sports in 63.4% of the injuries and a school in 21.4%. The most common diagnoses were a laceration (19.4%), strain or sprain (17.8%), contusion or abrasion (17.6%), or fracture (13.0%). The affected body part was 53.6% head and neck, 31.1% upper extremity, 8.0% trunk, 6.5% lower extremity, and 0.7% other/unknown. The patient was treated, released, or transferred in 98.3% of the injuries. CONCLUSION: The majority of patients were adolescents and male. Most of the injuries occurred at a place of recreation or sports or school. The most commonly reported injuries were laceration and strain or sprain and most often affected the head and neck.