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Reference intervals for the general clinical practice are expected to cover non-pathological values, but also reflect the underlying biological variation present in age- and gender-specific patient populations. Reference intervals can be inferred from routine patient data measured in high capacity using parametric approaches. Stratified reference distributions are obtained which may be transformed to normality via e.g. a Yeo-Johnson transformation. The estimation of the optimal transformation parameter for Yeo-Johnson through maximum likelihood can be highly influenced by the presence of outlying observations, resulting in biased reference interval estimates.

Aim: Three factors that affect the chemical composition and perceptible aroma of Retsina—a distinguished Greek wine, crafted by infusing resin harvested from the Aleppo pine (Pinus halepensis Mill.) into the fermentation process of white or rosé wines—were studied: i) the pine forest altitude (resins were harvested from two distinct forests), ii) the resins’ tapping method (two tapping methods were implemented; a conventional one using a paste of sulfuric acid on the pine trunk as an irritating stimulant, and a natural method by not using any chemical stimulant) and iii) the duration of resin extraction in the must (a short and a long extraction time were investigated). Methods: To study these three factors and their respective interactions, nine vinification protocols were carried out. Must and wine samples were collected at different time points during fermentation, maturation and after bottling, and analyzed by both headspace SPME-GC-MS and RP-LC-TIMS-TOF MS techniques. The findings of the chemical analyses were subsequently correlated with those of sensory analysis conducted. Results: In the case of pine resins harvested using the natural method, neither the forest microclimate, nor the employed duration of resin extraction in the must seem to affect the intensity of the oily character in the wine, which remains at low levels. On the other hand, the results showed that when pine resin is harvested by the conventional method, longer contact times release heavier and more oily aromas into the must. Conclusions: In the case of pine resin collected using the natural method, the extraction time in the wine must and the choice of the harvesting area of the resin do not constitute a factor of quality for the produced wine, but rather a matter of style, in contrast to conventionally harvested resin, where these factors are critical for the resulted quality.

Abstract Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Regular physical activity (PA) supports the long-term success of bariatric surgery. However, integrating health-enhancing physical activity in daily life requires specific competences. In this study, we evaluated a multimodal exercise programme to build these competences. Forty adults who underwent bariatric surgery were randomised to a multimodal exercise programme or control group. Primary outcomes were the facets of PA-related health competences, namely the control competence for physical training, PA-specific affect regulation, motivational competence and PA-specific self-control. Secondary outcomes were PA behaviour and subjective vitality. Outcomes were assessed before, directly after the intervention and at 3 months follow-up. Significant treatment effects were found for control competence for physical training and PA-specific self-control but not for PA-specific affect regulation and motivational competence. Significant treatment effects were further observed for self-reported exercise and subjective vitality, all in favour of the intervention group. In contrast, no treatment effect was found for device-based PA. Overall, this study provides a foundation for future research to optimise long-term post bariatric surgery outcomes., Author(s): Julia Schmid [sup.1] , Nina Schorno [sup.1] , André Groux [sup.2] , Daniel Giachino [sup.3] , Jörg Zehetner [sup.4] , Philip Nett [sup.5] , Christos T Nakas [sup.6] , [...]

Abstract Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and the most prevalent monogenic cause of autism. Although the knockout (KO) of the Fmr1 gene homolog in mice is primarily used for elucidating the neurobiological substrate of FXS, there is limited association of the experimental data with the pathophysiological condition in humans. The use of Fmr1 KO rats offers additional translational validity in this regard. Therefore, we employed a multi-level approach to study the behavioral profile and the glutamatergic and GABAergic neurotransmission status in pathophysiology-associated brain structures of Fmr1 KO rats, including the recordings of evoked and spontaneous field potentials from hippocampal slices, paralleled with next-generation RNA sequencing (RNA-seq). We found that these rats exhibit hyperactivity and cognitive deficits, along with characteristic bidirectional glutamatergic and GABAergic alterations in the prefrontal cortex and the hippocampus. These results are coupled to affected excitability and local inhibitory processes in the hippocampus, along with a specific transcriptional profile, highlighting dysregulated hippocampal network activity in KO rats. Overall, our data provide novel insights concerning the biobehavioral profile of FmR1 KO rats and translationally upscales our understanding on pathophysiology and symptomatology of FXS syndrome.

Background/Objectives: The relation between the orthopedic temporomandibular joint (TMJ) instability and temporomandibular disorder (TMD) most commonly remain unrecognized by orthodontists. In this study we aimed to evaluate the dentofacial characteristics and temporomandibular disorder symptomatology of patients with orthopedic instability before and after deprogramming with a stabilization splint. Methods: Sixty patients with the signs and symptoms of TMD were assessed using the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and underwent stabilization splint therapy to place the condyles in a more stable musculoskeletal position. The extent of condylar displacement was evaluated using the condylar position indicator (CPI). Sixteen angular and linear hard tissue landmarks were traced and compared from lateral cephalograms taken in the maximum intercuspation (MI) position before, and in the centric relation (CR) position after, the splint therapy. Results: Following the splint therapy, the signs and symptoms of TMD were significantly reduced or completely eliminated in more than 90% of patients. Compared with the values registered before the splint therapy, a significant reduction in the mean values of condylar displacement was observed on both sides of the vertical (p < 0.001), horizontal (p < 0.05), and transverse (p < 0.001) planes of space after the splint therapy. A comparison of pre- and post-splint lateral cephalograms revealed that, following the splint therapy, the mandible moved more posteriorly and rotated in a more clockwise direction. Conclusions: In patients with orthopedic instability and the signs and symptoms of TMD, muscle deprogramming with a stabilization splint therapy is highly recommended to improve the health of the temporomandibular joint and masticatory structures and contribute to a more correct orthodontic diagnosis.

Abstract Background Asymptomatic Plasmodium falciparum parasitaemia forms a reservoir for the transmission of malaria disease in West Africa. Certain haemoglobin variants are known to protect against severe malaria infection. However, data on the potential roles of haemoglobin variants and nongenetic factors in asymptomatic malaria infection is scarce and controversial. Therefore, this study investigated the associations of iron homeostasis, inflammation, nutrition, and haemoglobin mutations with parasitaemia in an asymptomatic cohort from a P. falciparum-endemic region during the high transmission season. Methods A sub-study population of 688 asymptomatic individuals (predominantly children and adolescents under 15 years, n = 516) from rural Burkina Faso previously recruited by the NOVAC trial (NCT03176719) between June and October 2017 was analysed. Parasitaemia was quantified with conventional haemocytometry. The haemoglobin genotype was determined by reverse hybridization assays targeting a selection of 21 HBA and 22 HBB mutations. Demographics, inflammatory markers (interleukins 6 and 10, hepcidin), nutritional status (mid upper-arm circumference and body mass index), and anaemia (total haemoglobin, ferritin, soluble transferrin receptor) were assessed as potential predictors through logistic regression. Results Malaria parasites were detected in 56% of subjects. Parasitaemia was associated most strongly with malnutrition. The effect size increased with malnutrition severity (OR = 6.26, CI95: 2.45–19.4, p

Age-specific and diurnal patterns of locomotory activity, can be considered as biomarkers of aging in model organisms and vary across the lifetime of individuals. Τhe Mediterranean fruit fly (medfly), Ceratitis capitata, is a commonly used model-species in studies regarding demography and aging. In the present study, we introduce a modification of the automated locomotory activity electronic device LAM25system (Locomotory Activity Monitor)-Trikinetics, commonly used in short time studies, to record the daily locomotory activity patterns of adult medflies throughout the life. Additionally, fecundity rates and survival of adult medflies were recorded. Male and female medflies were kept in the system tubes and had access to an agar-based gel diet, which provided water and nutrients. The locomotory activity was recorded at every minute by three monitors in the electronic device. The locomotory activity of females was higher than that of males across the different ages. For both sexes locomotory rates were high during the first 20 days of the adult life and decreased in older ages. The activity of males was high in the morning and late afternoon hours, while that of females was constantly high throughout the photophase. Negligible locomotory activity was recorded for both sexes during the nighttime. Males outlived females. Fecundity of females was higher in younger ages. Our results support the adoption of LAM25system in studies addressing aging of insects using medfly as a model organism.

Fusarium oxysporum f. sp. lentis (Fol) is considered the most destructive disease for lentil (Lens culinaris Medik.) worldwide. Despite the extensive studies elucidating plants’ metabolic response to fungal agents, there is a knowledge gap in the biochemical mechanisms governing Fol-resistance in lentil. Τhis study aimed at comparatively evaluating the metabolic response of two lentil genotypes, with contrasting phenotypes for Fol-resistance, to Fol-inoculation. Apart from gaining insights into the metabolic reprogramming in response to Fol-inoculation, the study focused on discovering novel biomarkers to improve early selection for Fol-resistance. GC-MS-mediated metabolic profiling of leaves and roots was employed to monitor changes across genotypes and treatments as well as their interaction. In total, the analysis yielded 178 quantifiable compounds, of which the vast majority belonged to the groups of carbohydrates, amino acids, polyols and organic acids. Despite the magnitude of metabolic fluctuations in response to Fol-inoculation in both genotypes under study, significant alterations were noted in the content of 18 compounds, of which 10 and 8 compounds referred to roots and shoots, respectively. Overall data underline the crucial contribution of palatinitol and L-proline in the metabolic response of roots and shoots, respectively, thus offering possibilities for their exploitation as metabolic biomarkers for Fol-resistance in lentil. To the best of our knowledge, this is the first metabolomics-based approach to unraveling the effects of Fol-inoculation on lentil’s metabolome, thus providing crucial information related to key aspects of lentil–Fol interaction. Future investigations in metabolic aspects of lentil–Fol interactions will undoubtedly revolutionize the search for metabolites underlying Fol-resistance, thus paving the way towards upgrading breeding efforts to combat fusarium wilt in lentil.

Clinical laboratories frequently conduct method verification studies to ensure that the process meets quality standards for its intended use, such as patient testing. They play a pivotal role in healthcare, but issues such as accurate statistical assessment and reporting of verification data often make these studies challenging. Missteps can lead to false conclusions about method performance, risking patient safety or leading to incorrect diagnoses. Despite a requirement for accredited labs to document method performance, existing solutions are often expensive and complex. Addressing these issues, we present Method Verification-Graphical User Interface (MV-GUI), a software package designed for ease of use. It is platform-independent, capable of statistical analysis, and generates accreditation-ready reports swiftly and efficiently. Users can input patient data from one or more .CSV files, and MV-GUI will produce comprehensive reports, including statistical comparison tables, regression plots, and Bland–Altman plots. While method validation, which establishes the performance of new diagnostic tools, remains a crucial concern for manufacturers, MV-GUI primarily streamlines the method verification process. The software aids both medical practitioners and researchers and is designed to be user-friendly, even for non-experienced users. Requiring no internet connection, MV-GUI can operate in restricted IT environments, making method verification widely accessible and efficient.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

P-values have played a central role in the advancement of research in virtually all scientific fields; however, there has been significant controversy over their use. “The ASA president’s task force statement on statistical significance and replicability” has provided a solid basis for resolving the quarrel, but although the significance part is clearly dealt with, the replicability part raises further discussions. Given the clear statement regarding significance, in this article, we consider the validity of p-value use for statistical inference as de facto. We briefly review the bibliography regarding the relevant controversy in recent years and illustrate how already proposed approaches, or slight adaptations thereof, can be readily implemented to address both significance and reproducibility, adding credibility to empirical study findings. The definitions used for the notions of replicability and reproducibility are also clearly described. We argue that any p-value must be reported along with its corresponding s-value followed by (1−α)% confidence intervals and the rejection replication index.

Response of endophytic fruit fly species (Tephritidae) to larval crowding is a form of scramble competition that may affect important life history traits of adults, such as survival and reproduction. Recent empirical evidence demonstrates large differences in adult life history traits, especially longevity, among Mediterranean fruit fly (Ceratitis capitata; "medfly") biotypes obtained from different regions of the world. However, whether the evolution of long lifespan is associated with response to stress induced by larval crowding has not been fully elucidated. We investigated, under constant laboratory conditions, the response of a short- and a long-lived medfly biotypes to stress induced by larval crowding. Survival and development of larvae and pupae and the size of resulting pupae were recorded. The lifespan and age-specific egg production patterns of the obtained adults were recorded. Our findings reveal that increased larval density reduced immature survival (larvae and pupae) in the short-lived biotype but had rather neutral effects on the longed-lived one. Only larvae of the long-lived biotype were capable of prolonging their developmental duration under the highest crowding regime to successfully pupate and emerge as adults. Response of emerging adults to larvae crowding conditions was similar in the two medfly biotypes. Those individuals emerging from high larval density regimes had reduced longevity and fecundity. Long-lived biotype individuals, however, appeared to suffer a higher cost in longevity compared with the short-lived one. The importance of our findings to understand the evolution of long lifespan is discussed.

Here we examined the feed and nutrient intake of captive small Indian civets (Viverricula indica) housed at the Chiang Mai Zoo (CMZ) and Demonstrated Farming Under Royal Project (DYF) in Ban Dong Yen in Thailand. The feed type and intake was recorded for 4 males and 5 females at both CMZ and DYF. Feed samples were collected for chemical analysis and nutrient intake was calculated in terms of dry matter (DM) to compare CMZ and DYF. There were 11 and 5 feed types at CMZ and DYF, respectively. DM intake of small Indian civets at CMZ was significantly lower than at DYF (32.84 ± 0.852 % vs 38.90 ± 0.184 %; P

This paper introduces a framework for online identification of cascading events in power systems with renewable generation, based on supervised machine learning techniques and measurement data. Cascading events are low-probability, high-impact events, the propagation of which can lead even to large-scale blackouts, with severe consequences to society. The proposed methodology is based on Long-short term memory networks, considering uncertainties associated with renewable generation, system loading and initial contingencies. By utilizing time-series measurement data, the proposed method can predict the appearance of cascading events, as defined by the discrete action of protection devices which can capture voltage, frequency or transient instability related dynamic phenomena. The proposed framework is applied on a modified version of the IEEE-39 bus model incorporating detailed dynamic renewable generation and protection devices implementations. Results highlight that the suggested method can successfully identify cases with cascading events with up to 95.6% accuracy and with an average inference time of 0.042s, taking into account practical considerations related to phasor measurement units, such as availability and noise in measurement data.

Introduction/Objective. Deprogramming of the neuromuscular system with the use of stabilization splint might provide more precise evaluation of the centric relation (CR) – maximum intercuspation (MI) discrepancy. The study aimed to evaluate the differences between the bite registrations obtained in the CR before and after the application of the stabilization splint therapy. Methods. The sample included 48 non-deprogrammed individuals without any apparent signs and symptoms of temporomandibular disorders (TMDs). The neuromuscular system was deprogrammed by employing stabilization splint therapy. A condylar displacement evaluation was performed on vertical, horizontal, and transverse planes of space, with the assistance of a condylar position indicator. Results. The mean values of condylar displacements, which were obtained after the deprogramming of the neuromuscular system, were significantly greater than those obtained before neuromuscular deprogramming for vertical condylar displacement (p < 0.0001). A greater degree of condylar distraction was observed on the left side of the vertical plane before (p < 0.01) and after neuromuscular deprogramming (p < 0.05). The highest level of condylar displacement occurred in the postero-inferior direction subsequent to the muscle deprogramming. Conclusion. It was observed that the level of average condylar displacements was significantly higher following the deprogramming of the neuromuscular system compared to that recorded before neuromuscular deprogramming using stabilization splint therapy. A more precise orthodontic diagnosis could have been obtained if the condyles were placed in a more exact CR position by muscle deprogramming.