Alternative Test Research Articles

Comprehensive Search for Genes Involved in Thalidomide Teratogenicity Using Early Differentiation Models of Human Induced Pluripotent Stem Cells: Potential Applications in Reproductive and Developmental Toxicity Testing

Developmental toxicity testing is essential to identify substances that may harm embryonic development. This study aimed to establish a protocol for evaluating developmental toxicity using human induced pluripotent stem cells (iPSCs) by analyzing cellular activity and gene expression changes. Two ICH S5(R3) positive substances, valproic acid (VPA), which is a substance previously detected as positive by other test methods, and thalidomide (Thalido), were examined during early trichoderm differentiation without fetal bovine serum. RNA-seq analysis identified seven candidate genes, including TP63, associated with altered expression following exposure to VPA or Thalido. These genes were implicated in pathways related to tissue development, cell growth, and molecular interactions. While the assay effectively detected VPA and Thalido, its limitations include testing only soluble substances and focusing on early differentiation stages. Nevertheless, the protocol demonstrates potential for the classification and evaluation of emerging modality drugs based on physical properties such as solubility, polarity, and pH. Integration with AI analysis may enhance its capacity to uncover genetic variations and evaluate previously uncharacterized substances. This study provides a foundation for alternative developmental toxicity testing methods, with further refinements in the culture method expected to improve accuracy and applicability in regulatory toxicology.

Mandatory ESG disclosure and trade credit: international evidence

ABSTRACT This study documents that worldwide mandatory ESG disclosure significantly increases firms’ use of trade credit. The baseline results hold across staggered differences-in-differences design, alternative samples test, dynamic effect model, and heterogeneity treatment analyses. Enhanced financial reporting quality and accounting conservatism are channels through which ESG disclosure affects trade credit. The baseline effect is stronger for disclosure initiated by stock exchanges, firms in civil law markets, firms in non-climate-vulnerable industries, and firms with lower market shares. These findings underscore the pivotal role of ESG disclosures in fostering trust and facilitating trade credit provision.

Navigating an Uninformative Genomic Test Result: A Practical Guide.

Although genomic testing is increasingly standard of care for diagnosing children and adults with genetic conditions, over 50% of genomic testing will return an uninformative result. To provide a practical guide for paediatricians on how to approach an uninformative genomic test result, and the pathways which may be available to uncover a genetic diagnosis for their patients. Input from multiple genetics healthcare professionals including genetic counsellors, the literature, and a general paediatrician were used to construct this guide. We also provide a hypothetical case vignette, to further demonstrate the various options for a patient after receiving an uninformative result. There are several reasons why an underlying genetic diagnosis may not be diagnosed with current testing, including incomplete phenotyping, a different underlying genetic mechanism requiring specialised testing, and limitations in knowledge at the time of the test. Uninformative results are very common, and it is important to understand these results in the context of the limitations of genomic testing. General paediatricians play an important role in supporting families through their diagnostic odyssey, as well as reassessing the phenotype, referring for sub-specialty inputs, and discussion with local genetics services for consideration of alternative testing options or enrolment into research pathways.

Abstract TMP109: Remote Ischemic Conditioning Treatment: A Study Report on Animal Stroke Model in Different Species, Sex, Age and Comorbidities from the Stroke Preclinical Assessment Network (SPAN)

Background: The Stroke Preclinical Assessment Network (SPAN), a multi-center network consisting of a coordinating center and testing laboratories, was created to enhance the rigor of preclinical research, including testing of potential therapies in animals of different species, sex, age, and co-morbidities, with blinding and randomization. SPAN evaluated six potential therapies with the goal of identifying one or more efficacious agents to advance toward a clinical trial. Remote ischemic post-conditioning (RIC) was selected as a candidate therapy for testing. Methods: In Stage I, young, healthy mixed-sex mice were randomized into treatment groups by the coordinating center. In Stage II, aged mice, mice with high-fat diet-induced obesity, and spontaneously hypertensive rats were utilized. Each stage included 25% of the study population and efficacy/futility was determined after each stage. RIC was bilaterally administered as the first session occurred immediately after reperfusion, and the second session occurred as close as possible to 12 ± 2 hours at post-MCAo, using an automated blood pressure cuff that delivered 200-mmHg to the hindlimbs for 4 cycles x 5 minutes/cycle and then once per day x 5 days under anesthesia. Sham-conditioned animals were treated with a cuff that did not inflate. The primary outcome measure was a modified corner test on days 7 and 30 post-stroke. MRI was performed at 48 hours and 30 days. Probabilistic index models, which adjusted for covariates of interest, were fit to estimate the probability of a lower corner test index (better outcome) between sham and RIC. Results: A total of 266 mice (132 sham, 134 RIC) were enrolled in the study, with 50 sham and 51 RIC-treated mice dying within 5 days of stroke. Analysis of all data revealed no significant differences in day 30 alternative corner test index between sham and RIC-treated mice after stroke in young, healthy mice (p=0.449), aged mice (p=0.079), mice with diet-induced obesity (p=0.135), or in spontaneously hypertensive rats (p=0.807). The secondary analysis found that RIC improved day 30 tissue infarction volume by MRI in young, healthy mice (p=0.024 vs. sham) but not in other co-morbid conditions. Conclusions: After advancing through Stages I and II, RIC was deemed futile at the end of Stage II, as determined by the modified corner test on day 30. The requirement for repeated daily general anesthesia during RIC administration may have been a complicated factor.

Automated strabismus detection and classification using deep learning analysis of facial images

Strabismus, or eye misalignment, is a common condition affecting individuals of all ages. Early detection and accurate classification are essential for proper treatment and avoiding long-term complications. This research presents a new deep-learning-based approach for automatically identifying and classifying strabismus from facial images. The proposed methodology leverages Convolutional Neural Networks (CNNs) to achieve high accuracy in both binary (strabismus vs. normal) and multi-class (eight-class deviation angle for esotropia and exotropia) classification tasks. The dataset for binary classification consisted of 4,257 facial images, including 1,599 normal cases and 2,658 strabismus cases, while the multi-class classification involved 480 strabismic and 142 non-strabismic images. These images were labeled based on ophthalmologist measurements using the Alternate Prism Cover Test (APCT) or the Modified Krimsky Test (MK). Five-fold cross-validation was employed, and performance was evaluated using sensitivity, accuracy, F1-score, and recall metrics. The proposed deep learning model achieved an accuracy of 86.38% for binary classification and 92.7% for multi-class classification. These results demonstrate the potential of our approach to assist healthcare professionals in early strabismus detection and treatment planning, ultimately improving patient outcomes.

Dairy intake and cognitive function in older adults in three cohorts: a mendelian randomization study.

Meta-analyses of observational studies on the effect of dairy on cognitive function have yielded inconclusive results, potentially due to unmeasured confounding. To avoid the no-unmeasured confounding assumption, we used lactase persistence genetic variant as an instrumental variable, for which the CC genotype is associated with lower lactase production and, consequently, lower dairy consumption. We used it to assess the effect of long-term consumption of total and non-fermented dairy on cognitive function. We included 43,836 individuals over 55 years old with genotyping, dietary data, and cognitive function measurements from three population-based studies: CoLaus|PsyCoLaus (Switzerland), the Rotterdam Study (the Netherlands) and the Canadian Longitudinal Study on Aging (CLSA - Canada). We performed a one-sample Mendelian randomization using two-stage least-squares regression. First, we estimated total and non-fermented dairy consumption by T-allele frequency. Second, we used the estimated dairy consumption in linear regression models on general cognition, assessed by the Mini-Mental State Examination (MMSE) and the Mental Alternation Test, executive function, verbal fluency, verbal learning, and memory. Per T-allele, total dairy intake and non-fermented was 24.8 and 15.3g/day higher in PsyCoLaus, 57.9 and 49.8g/day in the Rotterdam Study, and 0.31 and 0.29 times/day in CLSA, respectively. We found no association between the genetically predicted difference and the MMSE in PsyCoLaus and the Rotterdam Study. However, lactase persistent individuals scored 3.4 (95% CI2.1- 4.7) and 3.5 (95% CI 2.3-4.7) points more in the Mental Alternation Test for total and fermented dairy, respectively, in CLSA. Similarly, lactase persistent participants in CLSA had higher verbal fluency, verbal learning and executive function, but no differences were found in the other cohorts. Such inconsistencies might stem from different FFQs across cohorts and consumption ranges. Nonetheless, the generally small magnitude of effect sizes may suggest that there is no real effect between total or non-fermented dairy intake and cognitive function. The evidence for a causal effect of dairy consumption on general cognitive function is weak, consistent with previous results from classic analysis from observational studies. Interventions targeting dairy are unlikely to have a relevant effect on cognitive function.

Effects of Non-Feeding on Development in a Teleost, Minami-Medaka, Oryzias latipes: Identification of Eleutheroembryonic Stage for Potential Alternative Regulatory Toxicology Tests Along the 3R Principles.

Fish in the eleutheroembryonic life stage are defined as embryos or hatched fry before external self-feeding begins, and this stage is not classified as a protected life stage according to the EU (Directive 2010/63/EU) because of its alignment with the 3R principles (replacement, reduction, and refinement). In Minami-medaka (Oryzias latipes), the eleutheroembryonic stage is considered to extend until hatching, according to OECD TG210, whereas no supporting evidence to identify this stage has yet been reported. To clarify the medaka eleutheroembryonic stage, we investigated the effects of non-feeding on survival, growth, and gene expression in the NIES-R, Hd-rR, and d-rR strains. Non-feeding did not affect survival up to 6 days post-hatching (dph) in any strain, with survival rates exceeding 80%. However, non-feeding beyond 8 dph reduced the survival rates to below 50% at 30 dph. Fish growth, measured as total length, was not significantly affected by non-feeding up to 6 dph, except for the Hd-rR. Analysis of differentially expressed genes (DEGs) in response to non-feeding revealed that autophagy-related DEGs (wipi2, wdr45, wipi1, atg14, and map1lc3b) were found from 43 autophagy-related genes. map1lc3b and the other DEGs were upregulated after 4 and 6 days of non-feeding, respectively. However, the effect of non-feeding up to 6 dph was rescued by feeding. Together, the medaka fry < 6 dph were considered to be in the eleutheroembryonic stage for at least up to 4 dph, suggesting that hatched fry can be used to evaluate chemical toxicity and endocrine-disrupting activity according to the 3R principles. This study indicated that non-feeding did not affect survival up to 6 dph in NIES-R, Hd-rR, and d-rR strains of Minami-medaka, and fish growth was not affected by non-feeding up to 6 dph, except in the Hd-rR strain. Additionally, autophagy-related gene expression upregulated by non-feeding but was rescued by feeding. Together, we demonstrate for the first time that fry < 6 dph are in the eleutheroembryonic stage for at least up to 4 dph in Minami-medaka (Oryzias latipes).

The diagnostic accuracy and feasibility of paediatric visual field tests: A systematic review.

Alternative non-standard paediatric visual field (VF) tests have been developed to address the challenges associated with standard approaches. However, diagnostic accuracy of these new VF tests has not yet been rigorously evaluated. This systematic review aims to explore diagnostic accuracy and feasibility of non-standard VF tests in paediatric patients. The following databases were searched for English language studies comparing a non-standard paediatric VF test to standard methods, such as standard automated perimetry (SAP), manual kinetic perimetry (MKP) and confrontation testing (CT): EMBASE, PubMed, Ovid MEDLINE, Web of Science, Scopus, VisionCite, Cochrane Library, ClinicalTrials.gov, African Index Medicus, LILACS, Trip and grey literature databases. Studies included were of children ≤18 years old with suspected or known VF defects (n > 3). Case reports, case series, editorials and letters were excluded. This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Thirty studies (n = 2074 children, age range: 2 months to 18 years) published between 1990 and 2023 met the inclusion/exclusion criteria. Twenty index tests were reported, sorted into four categories of methods: behavioural/observational (5), electrophysiological (2), modifications of standard perimetry (11) and eye tracking (2). Risk of bias, based on the QUADAS-2 results, was unclear or high for most studies. Sensitivities of 10 studies (behavioural/observational [2]; electrophysiological [2]; modifications of standard perimetry [2] and eye tracking [4]) were 60%-100%, 75%, 80%-94% and 70%-100%, and specificities were 98%-100%, 86%-88%, 68%-100% and 50%-100%, respectively. Alternative non-standard paediatric VF tests, and behavioural/observational methods in particular, show potential for adequate diagnostic accuracy and feasibility, although limited to certain conditions and ages. Studies with complete reporting and low risk of bias are needed to determine the diagnostic accuracy and feasibility of non-standard paediatric VF tests.

A Novel Goodness-of-Fit Test for Lifetime Models Based on Type II Censored Data

In this paper, a novel test statistic is introduced to evaluate the goodness of fit of lifetime distributions when dealing with Type II censored data. The test statistic is derived from a local linear regression-based estimator of the Kullback–Leibler information. Extensive analysis is conducted to examine the properties of this test statistic, highlighting its nonnegative nature, as for KL information. The proposed test statistic is applied to various distributions, namely exponential, Weibull, log-normal, and Pareto. Critical values and Type I error rates for the tests are determined, demonstrating their exceptional accuracy and reliability. To further assess their performance, the proposed tests are subjected to Monte Carlo simulations, comparing their power values against alternative tests currently in use. Finally, the proposed method is applied to three real data sets from the engineering reliability aspect to prove their practical versatility.

Association between mixed exposure of non-persistent pesticides and liver fibrosis in the general US population: NHANES 2013-2016.

People are continually and simultaneously exposed to various non-persistent pesticides as these chemicals are ubiquitously distributed in the environment. Toxicological studies have indicated the associations between non-persistent pesticides and liver fibrosis in vitro and in vivo. However, epidemical study on the deleterious effect of non-persistent pesticides on the risk of liver fibrosis is rather limited. To examine the relationship between mixed non-persistent pesticides exposure and liver fibrosis, and to identify the potential pesticides of significant importance, this study enrolled the representative individuals from the NHANES 2013-2016 survey cycles, in which urinary non-persistent pesticides were measured. Liver fibrosis was determined based on the alternative noninvasive tests Fibrosis-4 index (FIB-4) and Hepamet Fibrosis Score (HFS). Survey-weighted linear/logistic regression and Bayesian kernel machine regression (BKMR) were used to detected the independent and combined associations between non-persistent pesticides and liver fibrosis, respectively. In single exposure analysis, significant and persistent associations were identified for 3,5,6-trichloropyridinol (TCPY), para-nitrophenol (PNP), glyphosate (GLYP) and 2,4-dichlorophenoxyacetic acid (2,4-D) exposure with both continuous and dichotomous liver fibrosis outcomes. Of them, TCPY and GLYP had the highest effect estimates, with the corresponding FIB-4 coefficient (β) being 0.09 (0.05-0.13, model 3) and 0.09 (0.06-0.12, model 3), respectively. In BKMR analysis, positive associations between pesticides mixture and FIB-4 and HFS liver fibrosis were identified. The results of Posterior Inclusion Probability (PIP) further showed that GLYP, TCPY, and PNP were the main contributors to the overall effects of pesticides mixture, and the corresponding PIPs were 1.000 (1.000), 1.000 (0.914) and 0.972 (0.819) for FIB-4 (HFS) liver fibrosis, respectively. This study indicates that exposure to non-persistent pesticides mixture is associated with increased risk of liver fibrosis in humans, and provide new insight into the hepatotoxic potential of non-persistent pesticides.

Analysis of the effect of congenital unilateral trochlear nerve paresis on retinal vascular density: a retrospective study.

To use swept-source optical coherence tomography angiography (SS-OCTA) to investigate the alterations in retinal vascular density (VD) in patients presenting with congenital unilateral trochlear nerve palsy. The medical records of patients diagnosed with congenital unilateral trochlear nerve palsy and those of a healthy control group were reviewed retrospectively. Comprehensive ocular examinations and SS-OCTA imaging were conducted. The study population was divided into three subgroups of eyes: paretic eyes, fellow eyes, and controls. All participants underwent comprehensive ophthalmic examinations, which included assessments of ocular motility, refraction under cycloplegia, and axial length measurement. Various strabismus tests-the cover-uncover test, prism and alternate cover test, Krimsky test, and Parks-Bielschowsky test-were conducted to confirm the diagnosis and evaluate the extent of the condition. A total of 34 patients and 39 healthy controls were included. Sex and age distributions were similar between groups. Significant differences were observed in central VD of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) between paretic eyes, fellow eyes, and control eyes. The fellow eye exhibited lower central VD compared to the paretic and control eyes. Inverse correlations between deviation angle and VD were noted in different SCP and DCP quadrants in paretic eyes. In our study cohort, there were significant changes in retinal VD in fellow eyes of patients with trochlear nerve palsy, which we speculate may be related to compensatory head position.

Approaches for estimating the unsaturated hydraulic conductivity of compacted quartz sand via particle packing theory

The unsaturated hydraulic conductivity (K) is one of the most important properties for evaluating moisture and gas migration in soil. However, the precise measurement of K in the laboratory often requires considerable time and economic costs. Currently, the most commonly used method to calculate K is to obtain it from the soil–water characteristic curve (SWCC) and saturated hydraulic conductivity. The void ratio e has a crucial influence on the variation in K. In this study, by combining two extended SWCC models (the Kwan model and the modified linear packing density model (MLPDM)) proposed by Liu et al. and two models (Model KS1 and Model KS2) for predicting the saturated hydraulic conductivity (KS) of compacted quartz sand, two approaches (Approach I and Approach II) for estimating the K of compacted quartz sand were proposed. A series of laboratory experiments (constant head permeability tests and alternative simplified evaporation tests) were conducted to verify and evaluate the accuracy and applicability of the two approaches for predicting the K values of compacted quartz sand. For Approach I, the average RMSE was 6.31 × 10− 6. For Approach II, the average RMSE was 5.82 × 10−6. Both Approach I and Approach II provided accurate and reasonable K values for 20 compacted quartz sand samples. Therefore, Approach I and Approach II can be used to predict moisture and gas migration in compacted quartz sand.

Dual-class share structure and financial constraints

Purpose This paper aims to examine the impact of dual-class share structures, where share structure is measured by the existence of a dual-class structure and also by excess voting rights and the proximity of the superior class shareholders in such structures, on financial constraints. Design/methodology/approach The study applies regression analyses to a sample of 2,466 observations on non-financial US firms over the period 2002–2018. The methods include regression with industry and year fixed effects, “propensity score matching” approach to match the dual-class firms with non-dual class firms and alternative measures of financial constraints. Findings The result shows that irrespective of how dual-class share structure is measured, it increases the level of financial constraints, except where dual-class share structure is measured by the proximity of superior class shareholders. Among the additional tests, the HM index has been used as a measure of financial constraints, and the findings show that the impact of dual-class structures on financial constraints appears to be driven by their effect on debt constraints. Finally, the findings are robust when the authors address endogeneity issues and remain consistent when the authors use alternative measures and tests. Practical implications The study has important implications for investors, regulators and policymakers, as it could help an understanding of the effect of the potential for conflict between superior class shareholders and other shareholders. Originality/value The results from the study support earlier literature on the impact of dual-class share structure on financial constraints. However, the study also provides new evidence on the different dimensions of dual-class share structure and financial constraints. Furthermore, the hand-collected data set on dual-class firms and the values of their voting wedge and the proximity of superior class shareholders may be useful to other researchers.

Oxytocin levels in response to CRH administration in hypopituitarism and hypothalamic damage: a randomized, crossover, placebo-controlled trial

Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in patients with hypopituitarism and hypothalamic damage (HHD), that might be associated with neuropsychological deficits and sexual dysfunction, leading to worse quality of life (QoL). Therefore, identifying a provocative test to diagnose an OXT-D will be important. Corticotropin-releasing hormone (CRH) is a candidate for such a test as it increases oxytocin secretion in animal models. This study aimed to examine the effects of CRH on oxytocin release in HHD compared to healthy controls (HC) and to describe the psychopathology, sexual function and QoL and their associations with oxytocin. This is a single-blind, randomized, placebo-controlled, proof-of-concept study (NCT 04902235) with crossover assignment (CRH vs. placebo). Nineteen HHD patients (10 females) and 20 HC (11 females) completed two visits, receiving CRH or placebo in random order and completed validated questionnaires to assess psychopathology, sexual function and QoL. Samples were collected over 120 min to assess oxytocin. Linear mixed-effects regression model evaluated the change in oxytocin after CRH/placebo in HHD vs. HC. CRH administration did not impact oxytocin concentrations across groups over time (p = 0.97). HHD had greater psychopathology (most ps < 0.05), sexual dysfunction (p < 0.03) and worse QoL (p < 0.001) compared to HC, nevertheless, baseline oxytocin concentrations and area under the curve of oxytocin were not significantly associated with psychopathology, sexual function or QoL, neither in HHD or HC. In conclusion, CRH administration does not appear to be a suitable provocative test for diagnosing OXT-D in HHD. Identifying a reliable diagnostic test for OXT-D remains crucial. Alternative provocative tests or biomarkers should be explored.

Microplastic Materials for Inhalation Studies: Preparation by Solvent Precipitation and Comprehensive Characterization.

Assessing the inhalation hazard of microplastics is important but necessitates sufficient quantity of microplastics that are representative and respirable (<4µm). Common plastics are not typically manufactured in such small sizes. Here, solvent precipitation is used to produce respirable test materials from thermoplastics polyurethane (TPU), polyamide (PA-6), polyethylene terephthalate (PET), and low-density polyethylene (LDPE). Complementary methods verified that the desired size range is achieved both in number metrics and in mass metrics. To assess if the test materials are representative of their original plastic, a range of molecular properties, particle properties, and impurities are characterized: chemical composition, molecular weight, crystallinity, molecular mobility, density, surface charge, surface reactivity, particle size in mass and number metrics, particle shape, endotoxin content, and solvent content. The test materials obtained by precipitation are compared to commercial granules as references, and to alternative test materials obtained by other synthesis routes from LDPE, TPU, PET, PA-6, polystyrene (PS), and polyvinylchloride (PVC). Charge and surface reactivity of the precipitated test materials are low. Due to storage in water, microbial contamination needed to be monitored. For PET, PA-6, and TPU, the test materials are considered as representative and fit for purpose, whereas the inherent hydrophobicity of LDPE imposed strong aggregation.

Implementing a Discrete Choice Experiment Within Consumer Sensory Evaluation to Better Understand Purchase Intention

ABSTRACTDiscrete choice experiments (DCE) offer a potential avenue to incorporate product specific contextual information into sensory consumer testing. This work integrates a taste variable into a DCE framework and compares the results against those obtained via traditional sensory methodology. Fruit puree taste profile was altered to induce taste variability while controlling confounding sensory variables. The taste levels were combined with extrinsic product specific attributes within a DCE. The same taste levels were also subjected to traditional overall liking rating. Comparison of the results showed the taste‐level preferences obtained via the DCE were consistent with those found via overall liking. The DCE was also capable of providing simultaneous insights into consumer preferences for extrinsic product attributes that were unable to be captured via the overall liking test. The results provide initial support for the usage of a DCE with an integrated taste variable as an alternative sensory consumer testing method.

Analyses of blood-derived host biomarkers for pulmonary tuberculosis diagnosis in human immunodeficiency virus co-infected individuals in sub-Saharan Africa: a systematic review and meta-analysis

ObjectiveOur objective was to conduct a review of host blood-derived biomarkers as potential diagnostic targets for pulmonary TB and as alternative tests to identify active tuberculosis in HIV co-infected individuals.MethodsA systematic review and meta-analysis of host blood-derived biomarkers with potential for diagnosis of active tuberculosis in HIV co-infected individuals was conducted. Cochrane Library, Embase, MEDLINE, PubMed and Web of Science databases were searched up to 7 November 2023. A hierarchical summary receiver operating characteristic (HSROC) model was used to evaluate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) of the following potential biomarkers: C-reactive protein (CRP), Interferon gamma induced protein-10 (IP-10), Neopterin, IGRA, Kynurenine to tryptophan (K/T) ratio and use of different panels of combined biomarkers; including 5 biomarker panel (IL-6, INF-y, MIG, CRP, and IL-18), 4 biomarker panel (IL-6, IL-21, INF-y, IL-1a), 6 biomarker panel (APO-ACIII, CXCL1, CXCL9, CCL8, CCL-1, and CD56), and 9 biomarker panel (Alpha-2-macroglobulin, fibrinogen, CRP, MMP-a, transthyretin, complement factor H, INF-y, IP-10, and TNF-α).ResultsTwenty-three studies were included. The pooled sensitivity of CRP, IP-10, Neopterin, combined biomarker signatures, IGRA and K/T ratio were 77% (60–88), 79% (72 - 84), 82% (43–96), 78% (64–88), 71% (65–76), 95% (90–98), respectively and the pooled specificity were 90% (80–96), 82% (59–93), 42% (22–66), 85% (73–92), 33% (18–54), and 95% (82–99), respectively.ConclusionCRP, IP-10, K/T ratio and the panels of multiple combined biomarkers that include the following cytokines, chemokines, and acute phase proteins IL-6, INF-y, MIG, CRP, IL-18, IL-21, IL-1a, APO-ACIII, CXCL1, CXCL9, CCL8, CCL-1, CD56, Alpha-2-macroglobulin, fibrinogen, MMP-a, transthyretin, complement factor H, IP-10, and TNF-α are potential blood biomarkers that can aid TB diagnosis in HIV co-infected individuals.

The Steep Ramp Test as Precursor to Assess Physical Fitness Before Esophagectomy in Cancer Patients.

Background Maximum oxygen uptake (VO₂max) is a predictor for postoperative complications after esophagectomy. Cardiopulmonary Exercise Test (CPET) is the golden standard for measuring VO₂max. The alternative Steep Ramp Test (SRT) is less strenuous with several benefits, providing an estimation of VO₂max. This study aims to determine whether SRT is a reliable alternative for CPET to evaluate preoperative fitness. Methods A total of 113 patients were included in this study. The agreement between SRT and CPET was analyzed using a t-test, Intraclass Correlation Coefficient (ICC), and the Bland-Altmann analysis. The threshold for adequate preoperative fitness was set at 17.0 ml/kg/min Results The mean difference between CPET and SRT was 2.77 ml/kg/min (95% CI 2.14-3.41). The ICC was 0.79 (95% CI 0.70-0.85). The upper limit of agreement of the Bland-Altmann was 9.44. The addition of 9.44 to the CPET-threshold gives an SRT-threshold of 26.44 ml/kg/min. Thirty-one (27.4%) patients scored higher than the SRT-threshold. Conclusion The SRT VO2max differs from VO₂max as measured by CPET. However, the difference was found to be clinically irrelevant for a substantial portion of patients. Hence, SRT is a promising alternative to CPET for determining physical fitness, and might render CPET obsolete for fit individuals.

Characterisation of the effects of the chemotherapeutic agent paclitaxel on neuropathic pain-related behaviour, anxiodepressive behaviour, cognition, and the endocannabinoid system in male and female rats.

Paclitaxel (PTX) is a commonly used chemotherapeutic drug, however, one of its major adverse effects is chronic neuropathic pain, with the incidence being higher in women than in men. The neurobiological mechanisms behind this sex difference are still largely unclear, and the endocannabinoid system, which exhibits sexual dimorphism and plays a key role in pain regulation, is a promising area for further studies. The present study aimed to characterise pain-, cognition-, anxiety-, and depression-related behaviours in male and female rats following PTX administration, and associated alterations in the endocannabinoid system. After the induction of the model, pain-related behaviours were assessed using von Frey, Acetone Drop and Hargreaves' tests, Novel Object Recognition and T-Maze Spontaneous Alternation tests were used for cognition-related behaviours, Elevated Plus Maze, Open Field, and Light Dark Box tests were used to assess anxiety-related behaviours, and Sucrose Preference, Sucrose Splash, and Forced Swim tests for depression-related behaviours. At each time point analysed, animals treated with PTX exhibited mechanical and cold hypersensitivity, with females displaying lower hind paw withdrawal thresholds to mechanical stimulation than males. No PTX-induced alterations in the other behavioural tests were detected. Post-mortem measurement of endocannabinoid and related N-acylethanolamine levels in spinal cord and discrete brain regions revealed a PTX-induced increase of 2-Arachidonoyl Glycerol (2-AG), N-Palmitoylethanolamine (PEA) and N-Oleoylethanolamine (OEA) levels in the amygdala of male and female animals, but not in the other areas. Collectively, these results suggest that PTX causes similar long-lasting hypersensitivity to mechanical and cold stimuli, but not heat, in rats of both sexes, effects accompanied by increases in amygdalar levels of endocannabinoids and N-acylethanolamines.

In vitro early proximal caries detection using trilateral short-wave infrared reflection at 1050 and 1550 nm.

This in vitro study evaluated the diagnostic potential of short-wave infrared reflection (SWIRR) at 1050 and 1550 nm for proximal caries detection from the occlusal, buccal, and lingual surfaces of posterior teeth under clinically relevant conditions. Bitewing radiography (BWR) was the alternative index test and micro-computed tomography (μCT) was the reference standard. Two hundred and fifty proximal surfaces of extracted human teeth were examined using SWIRR at 1050 and 1550 nm and BWR. SWIRR, BWR, and μCT findings were evaluated twice by 2 trained examiners. SWIRR images were evaluated from occlusal and trilateral (occlusal, buccal, and lingual combined) views. Sensitivity, specificity, and area under the curves were calculated. Reliability assessment was performed using κ statistics. Short-wave infrared reflection (1050 nm) showed sensitivity of 0.44 for occlusal and 0.55 for trilateral assessment, paired with specificity of 0.96 and 0.90, whereas SWIRR (1550 nm) showed sensitivity of 0.73 and 0.85 paired with specificity of 0.76 and 0.59. Compared to occlusal view, trilateral SWIRR view revealed ≈10% higher sensitivity and lower specificity. BWR revealed lowest sensitivity (0.30) and highest specificity (0.99). Over- and underestimation of caries demonstrated opposite trends: from 1050 to 1550 nm, overestimation of trilateral SWIRR increased (0.08-0.29), while underestimation decreased (0.15-0.06). Trilateral SWIRR has higher sensitivity and lower specificity for proximal caries, than occlusal SWIRR. For trilateral SWIRR, wavelengths around 1050 nm are more suitable, while 1550 nm is better for occlusal examinations. A combination of SWIRR at 1050 and 1550 nm may exhibit a balanced sensitivity and specificity for proximal caries.