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While there is great potential for unbiased next-generation sequencing (NGS) approaches—eg, whole transcriptome sequencing (WTS)—for exploration, discovery, and clinical application in the realm of oncology, there are limitations that should be considered when relying on these methodologies for clinical decision making. When using WTS for the detection of clinically relevant gene fusions in tumor specimens, a key consideration is whether a limited coverage depth (approximately 30-50X) is sufficient for detecting these events, especially in samples with low tumor purity. We demonstrate the reduced sensitivity of both a commercial WTS assay for the detection of clinically relevant fusions in analytical validation control samples and of a research use only (RUO) WTS assay for the detection of clinically relevant fusions in real-world clinical samples compared to RNA comprehensive genomic profiling (CGP). Notably, the RUO WTS assay would not have reported 30% (6/20) of fusions detected using RNA CGP assays in fusion-positive tumor samples, highlighting a potential disadvantage of broader sequencing. [ABSTRACT FROM AUTHOR]

The Persian silk tree (Albizia julibrissin) has delicate flowers with a pleasant aroma profile, displaying notes of hyacinth and rose with subtle nuances of citrus, coconut and spice. In this study, a total of 29 odorants were identified in the flowers from a single A. julibrissin selection by the application of a cold‐solvent extraction (CSE), followed by solvent‐assisted flavour evaporation (SAFE) and aroma extract dilution analysis (AEDA). Subsequently, nine odorants with flavour dilution (FD) factors ≥16 were quantitated by stable isotope dilution analysis (SIDA), and odour activity values (OAVs) were calculated. Odorants with OAV ≥1 included 2‐phenylacetaldehyde (OAV 3638), linalool (OAV 797), eugenol (OAV 231), geraniol (OAV 161), 1H‐indole (OAV 93), β‐ionone (OAV 31), 2‐phenylethanol (OAV 11) and γ‐octalactone (OAV 1). An aroma simulation model was prepared based on the quantitation data, and it closely matched the aroma of the flower isolate. Chiral chromatography was performed, and (S)‐(+)‐linalool was the only enantiomer detected. This study advances our understanding of A. julibrissin flower aroma chemistry and lays the groundwork for future investigations for the development of delicate floral aromas for flavour and fragrance applications. [ABSTRACT FROM AUTHOR]

Background: Every year 2% of pregnant women undergo nonobstetric surgical interventions worldwide. According to the American College of Obstetricians and Gynecologists Committee on Obstetric Practice, pregnant women should never be denied the most appropriate surgical treatment, regardless of the trimester of pregnancy. However, additional attention should be paid during the first trimester since it has the highest risk of inducing teratogenic mutations; additionally, during the third trimester, due to the possibility of preterm birth and low birth weight of the newborn, great care should be paid. Case presentation: We present the case of a Caucasian 36-year-old woman during her 21st week of pregnancy, with a normal-sized fetus, according to the gestational age on ultrasound exam, and with no additional risk factors. The patient referred to an increasing nasal obstruction associated with rhinorrhea of the left nasal cavity. She also reported episodes of sleep apnea and hyposmia. The patient received a detailed otolaryngological examination, which allowed for identification of a mass within the left nasal cavity. The subsequent nasal endoscopy confirmed a grayish polypoid mass lesion with a multinodular surface occupying the entire left nasal fossa. The lesion totally obliterated the left maxillary sinus, resulting in obstruction of the anterior osteomeatal unit and ethmoidal sinusitis. She was referred for a functional endoscopic sinus surgery using analgosedation with remifentanil target-controlled infusion. Discussion and conclusion: To the very best of our knowledge, this is the first case described in English literature about the use of analgosedation with remifentanil target-controlled infusion for otolaryngology surgery, specifically in functional endoscopic sinus surgery. It could be an interesting option to avoid the use of inhaled anesthetics that could induce fetal damage, especially during the first months of pregnancy. Furthermore, patient intubation is not necessary, which avoids cases of difficult intubation or any trauma to the airways. An adequate informed consent and appropriate compliance are elements of paramount importance in tailoring the anesthetic strategy for pregnant women who need nonobstetric surgical management. [ABSTRACT FROM AUTHOR]

Background: Adolescence is a period of heightened vulnerability to developing mental health problems, and rates of mental health disorder in this age group have increased in the last decade. Preventing mental health problems developing before they become entrenched, particularly in adolescents who are at high risk, is an important research and clinical target. Here, we report the protocol for the trial of the 'Building Resilience through Socioemotional Training' (ReSET) intervention. ReSET is a new, preventative intervention that incorporates individual-based emotional training techniques and group-based social and communication skills training. We take a transdiagnostic approach, focusing on emotion processing and social mechanisms implicated in the onset and maintenance of various forms of psychopathology. Methods: A cluster randomised allocation design is adopted with randomisation at the school year level. Five-hundred and forty adolescents (aged 12–14) will be randomised to either receive the intervention or not (passive control). The intervention is comprised of weekly sessions over an 8-week period, supplemented by two individual sessions. The primary outcomes, psychopathology symptoms and mental wellbeing, will be assessed pre- and post-intervention, and at a 1-year follow-up. Secondary outcomes are task-based assessments of emotion processing, social network data based on peer nominations, and subjective ratings of social relationships. These measures will be taken at baseline, post-intervention and 1-year follow-up. A subgroup of participants and stakeholders will be invited to take part in focus groups to assess the acceptability of the intervention. Discussion: This project adopts a theory-based approach to the development of a new intervention designed to target the close connections between young people's emotions and their interpersonal relationships. By embedding the intervention within a school setting and using a cluster-randomised design, we aim to develop and test a feasible, scalable intervention to prevent the onset of psychopathology in adolescence. Trial registration: ISRCTN88585916. Trial registration date: 20/04/2023. [ABSTRACT FROM AUTHOR]

Background: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. Objectives: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. Methods: A 6‐week randomised, crossover, double‐blinded and placebo‐controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. Results: Between December 2014 and 2017, 22 participants were recruited – 20 completed both arms, and 21 were analysed. The pump was well‐tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid‐sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. Conclusions: These findings support the administration of hormone therapy that mimics physiology. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Nicotine-containing products (NCPs) such as electronic nicotine delivery systems (ENDS) are increasingly common throughout the landscape of youth use of nicotine-containing products (NCP), and have overtaken traditional cigarette smoking modalities. This study seeks to examine the genetic and environmental influences on liability for susceptibility and initiation of ENDS and other NCPs among US children. METHODS: Data were drawn from 886 monozygotic (MZ) and dizygotic (DZ) twin pairs aged 9-10 years in the Adolescent Brain & Cognitive Development (ABCD) study at the baseline during 2016-2018. Heritability (h²) measured the proportion of the total phenotypic variation attributable to genes. Variance component models were utilized to analyze influences from the common environment (c²) and unique environmental factors (e²), taking into account correlations within twin pairs. RESULTS: The national sample included 50% females, 69.5% of non-Hispanic Whites, 12.8% of non-Hispanic Blacks, and 11.6% of Hispanics, with a mean age of 121.5 months. The twin sets were 60% DZ and 40% MZ. Heritability was low for NCP susceptibility (h²=0) and moderate for NCP initiation (h²=39%, p=0.02). The variance associated with NCP susceptibility was primarily influenced by environmental factors, especially one's unique factors (c²=37%, p<0.0001 vs e²=63%, p<0.0001). In contrast, the variance associated with NCP initiation was split across common and unique environmental factors (c²=32%, p=0.02 vs e²=29%, p=0.02). CONCLUSIONS: In the era with ENDS use surging among youth, NCP initiation remains to be a heritable trait with joint influence from the environment. NCP susceptibility is largely influenced by environmental factors, especially unique environments. Continued assessment of gene × environment interaction can better inform future youth NCP interventions. [ABSTRACT FROM AUTHOR]

Understanding how host-associated microbial assemblages respond to pathogen invasion has implications for host health. Until recently, most investigations have focused on understanding the taxonomic composition of these assemblages. However, recent studies have suggested that microbial assemblage taxonomic composition is decoupled from its function, with assemblages being taxonomically varied but functionally constrained. The objective of this investigation was to understand how the Tri-colored bat, Perimyotis subflavus cutaneous microbial assemblage responds to fungal pathogen invasion within a functional context. We hypothesized that at a broad scale (e.g., KEGG pathways), there will be no difference in the functional assemblages between the white nose pathogen, Pseudogymnoascus destructans, positive and negative bats; and this pattern will be driven by the functional redundancy of bacterial taxa. At finer scales (e.g., gene models), we postulate differences in function attributed to interactions between bacteria and P. destructans, resulting in the production of antifungal metabolites. To test this, we used a combination of shotgun metagenomic and amplicon sequencing to characterize the bat cutaneous microbial assemblage in the presence/absence of P. destructans. Results showed that while there was a shift in taxonomic assemblage composition between P. destructans positive and negative bats, there was little overall difference in microbial function. Functional redundancy across bacterial taxa was clear at a broad-scale; however, both redundancy and variation in bacterial capability related to defense against pathogens was evident at finer scales. While functionality of the microbial assemblage was largely conserved in relation to P. destructans, the roles of particular functional pathways in resistance to fungal pathogens require further attention. [ABSTRACT FROM AUTHOR]

PURPOSE: A semiautomated pipeline for the collection and curation of free-text and imaging real-world data (RWD) was developed to quantify cancer treatment outcomes in large-scale retrospective real-world studies. The objectives of this article are to illustrate the challenges of RWD extraction, to demonstrate approaches for quality assurance, and to showcase the potential of RWD for precision oncology. METHODS: We collected data from patients with advanced melanoma receiving immune checkpoint inhibitors at the Lausanne University Hospital. Cohort selection relied on semantically annotated electronic health records and was validated using process mining. The selected imaging examinations were segmented using an automatic commercial software prototype. A postprocessing algorithm enabled longitudinal lesion identification across imaging time points and consensus malignancy status prediction. Resulting data quality was evaluated against expert-annotated ground-truth and clinical outcomes obtained from radiology reports. RESULTS: The cohort included 108 patients with melanoma and 465 imaging examinations (median, 3; range, 1-15 per patient). Process mining was used to assess clinical data quality and revealed the diversity of care pathways encountered in a real-world setting. Longitudinal postprocessing greatly improved the consistency of image-derived data compared with single time point segmentation results (classification precision increased from 53% to 86%). Image-derived progression-free survival resulting from postprocessing was comparable with the manually curated clinical reference (median survival of 286 v 336 days, P =.89). CONCLUSION: We presented a general pipeline for the collection and curation of text- and image-based RWD, together with specific strategies to improve reliability. We showed that the resulting disease progression measures match reference clinical assessments at the cohort level, indicating that this strategy has the potential to unlock large amounts of actionable retrospective real-world evidence from clinical records. Our semiautomated pipeline captures real-world tumor evolution from retrospective PET-CT scans. [ABSTRACT FROM AUTHOR]

Background: Although autism and callous‐unemotional (CU) traits are distinct conditions, both are associated with difficulties in emotion recognition. However, it is unknown whether the emotion recognition difficulties characteristic of autism and CU traits are driven by comparable underpinning mechanisms. Methods: We tested whether cueing to the eyes improved emotion recognition in relation to autistic and CU traits in a heterogeneous sample of children enhanced for social, emotional and behavioural difficulties. Participants were 171 (n = 75 male) children aged 10–16 years with and without a diagnosis of autism (n = 99 autistic), who completed assessments of emotion recognition with and without cueing to the eyes. Parents completed the assessment of autistic and CU traits. Results: Associations between autistic and CU traits and emotion recognition accuracy were dependent upon gaze cueing. CU traits were associated with an overall decrease in emotion recognition in the uncued condition, but better fear recognition when cued to the eyes. Conversely, autistic traits were associated with decreased emotion recognition in the cued condition only, and no interactions between autistic traits and emotion were found. Conclusions: The differential effect of cueing to the eyes in autistic and CU traits suggests different mechanisms underpin emotion recognition abilities. Results suggest interventions designed to promote looking to the eyes may be beneficial for children with CU traits, but not for children with autistic characteristics. Future developmental studies of autism and CU characteristics are required to better understand how different pathways lead to overlapping socio‐cognitive profiles. [ABSTRACT FROM AUTHOR]

One of the objectives of oncology phase I dose‐escalation studies has been to determine the maximum tolerated dose (MTD). Although MTD is no longer set as the dose for further development in contemporary oncology drug development, MTD determination is still important for informing the therapeutic index. Bayesian adaptive model‐based designs are becoming mainstream in oncology first‐in‐human trials. Herein, we illustrate via simulations the use of systemic exposure in Bayesian adaptive dose–toxicity models to estimate MTD. We extend traditional dose–toxicity models to incorporate pharmacokinetic exposure, which provides information on exposure–toxicity relationships. We pursue dose escalation until the maximum tolerated exposure (corresponding to the MTD) is reached. By leveraging pharmacokinetics, dose escalation considers exposure and interindividual variability on a continuous rather than discrete domain, offering additional information for dose‐escalation decisions. To demonstrate this, we generated 1000 simulations (starting dose of 1/25th the reference dose and six dose levels) for several different scenarios. Both rule‐based and model‐based designs were compared using metrics of potential safety, accuracy, and reliability. The mean results over simulations and different toxicity scenarios showed that model‐based designs were better than rule‐based methods and that exposure–toxicity model‐based methods have the potential to valuably complement dose–toxicity model‐based methods. Exposure–toxicity model‐based methods had decreased underdose risk accompanied by a relatively smaller increase in overdose risk, resulting in improved net reliability. MTD estimation accuracy was compromised when exposure variability was large, emphasizing the importance of appropriate control of pharmacokinetic variability in phase I dose‐escalation studies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is among the most common autoimmune disabling neurological conditions of young adults and affects more than 2.3 million people worldwide. Predicting future disease activity in patients with MS based on their pathophysiology and current treatment is pivotal to orientate future treatment. In this respect, we used machine learning to predict disease activity status in patients with MS and identify the most predictive covariates of this activity. The analysis is conducted on a pooled population of 1935 patients enrolled in three cladribine tablets clinical trials with different outcomes: relapsing–remitting MS (from CLARITY and CLARITY‐Extension trials) and patients experiencing a first demyelinating event (from the ORACLE‐MS trial). We applied gradient‐boosting (from XgBoost library) and Shapley Additive Explanations (SHAP) methods to identify patients' covariates that predict disease activity 3 and 6 months before their clinical observation, including patient baseline characteristics, longitudinal magnetic resonance imaging readouts, and neurological and laboratory measures. The most predictive covariates for early identification of disease activity in patients were found to be treatment duration, higher number of new combined unique active lesion count, higher number of new T1 hypointense black holes, and higher age‐related MS severity score. The outcome of this analysis improves our understanding of the mechanism of onset of disease activity in patients with MS by allowing their early identification in clinical settings and prompting preventive measures, therapeutic interventions, or more frequent patient monitoring. [ABSTRACT FROM AUTHOR]

Cladribine tablets have been approved in many countries for the treatment of patients with various forms of relapsing multiple sclerosis (MS). Cladribine has a unique pharmacokinetic/pharmacodynamic (PK/PD) profile with a short elimination half‐life (~ 1 day) relative to a prolonged PD effect on specific immune cells (most notably a reversible reduction in B and T lymphocyte counts). This results in a short dosing schedule (up to 20 days over 2 years of treatment) to sustain efficacy for at least another 2 years. Global clinical studies were conducted primarily in White patients, in part due to the distinctly higher prevalence of MS in White patients. Given the very low prevalence in Asian countries, MS is considered as a rare disease there. In spite of the limited participation of Asian patients, to demonstrate favorable benefit/risk profile in the treatment of MS demanded application of a Totality of Evidence approach to assess ethnic sensitivity for informing regulatory filings in Asian countries and supporting clinical use of cladribine in Asian patients. Population PD modeling and simulation of treatment‐related reduction in absolute lymphocyte count, as a mechanism‐related biomarker of drug effect, confirmed consistent PDs in Asian and non‐Asian patients with MS, supporting absence of ethnic sensitivity and a common dosage across populations. Through this example, we demonstrate the value of holistic integration of all available data using a model‐informed drug development (MIDD) framework and a Totality of Evidence mindset to evaluate ethnic sensitivity in support of Asia‐inclusive development and use of the drug across populations. [ABSTRACT FROM AUTHOR]

Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad®), administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years), are used to treat patients with relapsing multiple sclerosis. Cladribine has been shown to be a substrate of various nucleoside transporters (NTs). Intestinal absorption and distribution of cladribine throughout the body appear to be essentially mediated by equilibrative NTs (ENTs) and concentrative NTs (CNTs), specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Other efficient transporters of cladribine are the ABC efflux transporters, specifically breast cancer resistance protein, which likely modulates the oral absorption and renal excretion of cladribine. A key transporter for the intracellular uptake of cladribine into B and T-lymphocytes is ENT1 with ancillary contributions of ENT2 and CNT2. Transporter-based drug interactions affecting absorption and target cellular uptake of a prodrug such as cladribine are likely to reduce systemic bioavailability and target cell exposure, thereby possibly hampering clinical efficacy. In order to manage optimized therapy, i.e., to ensure uncompromised target cell uptake to preserve the full therapeutic potential of cladribine, it is important that clinicians are aware of the existence of NT-inhibiting medicinal products, various lifestyle drugs, and food components. This article reviews the existing knowledge on inhibitors of NT, which may alter cladribine absorption, distribution, and uptake into target cells, thereby summarizing the existing knowledge on optimized methods of administration and concomitant drugs that should be avoided during cladribine treatment. [ABSTRACT FROM AUTHOR]

Estimated genetic associations with prognosis, or conditional on a phenotype (e.g. disease incidence), may be affected by collider bias, whereby conditioning on the phenotype induces associations between causes of the phenotype and prognosis. We propose a method, 'Slope-Hunter', that uses model-based clustering to identify and utilise the class of variants only affecting the phenotype to estimate the adjustment factor, assuming this class explains more variation in the phenotype than any other variant classes. Simulation studies show that our approach eliminates the bias and outperforms alternatives even in the presence of genetic correlation. In a study of fasting blood insulin levels (FI) conditional on body mass index, we eliminate paradoxical associations of the underweight loci: COBLLI; PPARG with increased FI, and reveal an association for the locus rs1421085 (FTO). In an analysis of a case-only study for breast cancer mortality, a single region remains associated with more pronounced results. Genetic associations can be biased by conditioning on a phenotype. This study presents 'Slope-Hunter', a method which uses model-based clustering to correct this bias, even in the presence of genetic correlation, assuming the class of SNPs affecting only the collider explains more variation in the collider than any other class of SNPs. [ABSTRACT FROM AUTHOR]

Cladribine is a nucleoside analog that is phosphorylated in its target cells (B- and T-lymphocytes) to its active adenosine triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad®) administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years) are used to treat patients with relapsing multiple sclerosis. The ATP-binding cassette, solute carrier, and nucleoside transporter substrate, inhibitor, and inducer characteristics of cladribine are reviewed in this article. Available evidence suggests that the distribution of cladribine across biological membranes is facilitated by a number of uptake and efflux transporters. Among the key ATP-binding cassette efflux transporters, only breast cancer resistance protein has been shown to be an efficient transporter of cladribine, while P-glycoprotein does not transport cladribine well. Intestinal absorption, distribution throughout the body, and intracellular uptake of cladribine appear to be exclusively mediated by equilibrative and concentrative nucleoside transporters, specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Renal excretion of cladribine appears to be most likely driven by breast cancer resistance protein, ENT1, and P-glycoprotein. The latter may play a role despite its poor cladribine transport efficiency in view of the renal abundance of P-glycoprotein. There is no evidence that solute carrier uptake transporters such as organic anion transporting polypeptides, organic anion transporters, and organic cation transporters are involved in the transport of cladribine. Available in vitro studies examining the inhibitor characteristics of cladribine for a total of 13 major ATP-binding cassette, solute carrier, and CNT transporters indicate that in vivo inhibition of any of these transporters by cladribine is unlikely. [ABSTRACT FROM AUTHOR]

Aim: Produce empirical support for further enhancements to a therapy selection protocol for obstructive sleep apnea (OSA) patients intolerant of positive airway pressure. Methods: A retrospective analysis was conducted in 101 men and 69 women patients. Two-night home sleep apnea studies were conducted at baseline and with a trial oral appliance. Twenty-minutes in-position sleep was required to compute supine and non-supine apnea-hypopnea indexes (AHI). Data analyses were applied after stratification by sex and response to oral appliance therapy (OAT), and the results used for to calculate incremental cost-effectiveness ratios (ICER). Results:: Compared with men, women had significantly lower pre-treatment supine and non-supine AHI values (p<.05). OAT non-responders had higher non-supine AHIs, resulting in less positional-OSA and more cases with severe OSA (p<.05). Across the cohort, 21% had positional-OSA with a pre-treatment non-supine AHI < 5 events/h. In those who met this criterion, supine avoidance therapy (SAT) could have reduced the AHI values more than OAT by an average of 33% (p<.0001). The ICER for SAT instead of OAT in this group was negative, a condition that only occurs when one therapy is both less expensive and more effective than the other. A greater proportion of non-responders had post-OAT overall AHI ≥ 10 events/h with residual positional-OSA compared with responders (p<.0001). Combination therapy could reduce the AHI values by an average of 68%, resulting in ICER estimates five-times less than the reimbursement decision-making threshold. Conclusions and limitations: Based on pre-treatment non-supine AHI values, SAT would provide a superior first-line treatment outcome as compared to OAT in 21% of patients diagnosed with OSA. SAT would also provide a cost-effective adjuvant to OAT in an additional 15% of cases. The benefit of SAT could not be determined in one-fifth of the cohort who slept exclusively supine. [ABSTRACT FROM AUTHOR]

The desire to conduct research in the Arctic on an ever-larger spatiotemporal scale has led to the development of long-range autonomous underwater vehicles (AUVs), such as the Autosub Long-Range 1500 (ALR1500). While these platforms open up a world of new applications, their actual use is limited in GPS-denied environments since self-contained navigation remains yet unavailable. In response, this study evaluates whether terrain-aided navigation (TAN) can enable multimonth deployments using basic navigation sensors and sparse bathymetric maps. To evaluate the potential, ALR1500 undertakes a hypothetical science-driven mission from Svalbard (Norway) to Point Barrow (Alaska, USA) under the sea ice (a mission over 3200 km). Therefore, a simulated environment is developed, which integrates a state-of-the-art model of water circulation, error models for heading estimation at high latitudes, and an Arctic bathymetric map. Recognizing that this map is constructed based on sparse depth measurements and interpolation techniques, a bathymetric uncertainty model is developed. The performance of the TAN algorithm is examined with respect to the type of the heading sensor utilized and a range of vertical map distortions, calculated using the developed bathymetric uncertainty model. Simulations show that unaided navigation experiences an error of hundreds of kilometers, whereas TAN provides acceptable accuracy given a moderate map distortion. By degrading the quality of the map further, it appears that the navigation filter may diverge when traversing large regions subject to interpolation. Therefore, a rapidly-exploring random tree star algorithm is used to design a new path such that the AUV traverses reliable and rich in topographic information areas. [ABSTRACT FROM AUTHOR]

Bacillus strain UTK D1-0055 was isolated from a laboratory environment and appeared to have antilisterial activity. The genome was sequenced, the strain was identified as Bacillus altitudinis, and a high-quality complete annotated genome was produced. The taxonomy was evaluated for this and related Bacillus species (B. aerophilus, B. pumilus, B. safensis, B. stratosphericus, and B. xiamenensis) because the taxonomy is unclear and contains errors in public databases such as NCBI. The included strains grouped into seven clusters based on average nucleotide identity. Strains designated as B. aerophilus, B. altitudinis, and B. stratosphericus grouped together in the cluster containing the B. altitudinis type strain, suggesting that these three species should be considered a single species, B. altitudinis. The antimicrobial activity of UTK D1-0055 was evaluated against a panel of 15 Listeria strains (nine Listeria monocytogenes serotypes, Listeria innocua, and Listeria marthii), other foodborne pathogens (six Salmonella enterica serotypes and Escherichia coli), and three representative fungi (Saccharomyces cerevisiae, Botrytis cinerea, and Hyperdermium pulvinatum). Antibacterial activity was observed against all Listeria strains, but no antibacterial effects were found against the other tested bacterial and fungal strains. Biosynthetic gene clusters were identified in silico that may be related to the observed antibacterial activity, and these clusters included genes that putatively encode bacteriocins and nonribosomally synthesized peptides. The B. altitudinis strain identified in this investigation had a broad range of antilisterial activity, suggesting that it and other related strains may be useful for biocontrol in the food industry. [ABSTRACT FROM AUTHOR]

Produce empirical support for further enhancements to a therapy selection protocol for obstructive sleep apnea (OSA) patients intolerant of positive airway pressure. A retrospective analysis was conducted in 101 men and 69 women patients. Two-night home sleep apnea studies were conducted at baseline and with a trial oral appliance. Twenty-minutes in-position sleep was required to compute supine and non-supine apnea-hypopnea indexes (AHI). Data analyses were applied after stratification by sex and response to oral appliance therapy (OAT), and the results used for to calculate incremental cost-effectiveness ratios (ICER). Compared with men, women had significantly lower pre-treatment supine and non-supine AHI values (p <.05). OAT non-responders had higher non-supine AHIs, resulting in less positional-OSA and more cases with severe OSA (p <.05). Across the cohort, 21% had positional-OSA with a pre-treatment non-supine AHI < 5 events/h. In those who met this criterion, supine avoidance therapy (SAT) could have reduced the AHI values more than OAT by an average of 33% (p <.0001). The ICER for SAT instead of OAT in this group was negative, a condition that only occurs when one therapy is both less expensive and more effective than the other. A greater proportion of non-responders had post-OAT overall AHI ≥ 10 events/h with residual positional-OSA compared with responders (p <.0001). Combination therapy could reduce the AHI values by an average of 68%, resulting in ICER estimates five-times less than the reimbursement decision-making threshold. Based on pre-treatment non-supine AHI values, SAT would provide a superior first-line treatment outcome as compared to OAT in 21% of patients diagnosed with OSA. SAT would also provide a cost-effective adjuvant to OAT in an additional 15% of cases. The benefit of SAT could not be determined in one-fifth of the cohort who slept exclusively supine. [ABSTRACT FROM AUTHOR]

There are key unanswered questions when it comes to multicomponent odor discrimination. This study was designed to assess discrimination of odorant mixtures that elicit a singular percept. We collected data to address the following two questions: (1) What odor features do humans notice when attempting to discriminate between subtly different odor mixtures? (2) Are odor mixtures easier to discriminate when an odorant is added, compared with when a component is removed? Using modern aroma chemistry techniques, an odor mixture resembling a generic white wine was constructed. This wine odor mixture was modified using a series of three esters which are commonly found in white wines that vary in chain length and branching. Participants performed a sequence of discrimination tasks for the addition/subtraction of modifiers to the base wine at different concentrations. Only one of the esters (ethyl propanoate) led to a discriminable odor mixture. As concentration of the modifying odorant was increased, discrimination of odor mixtures was first reported because of changes in odor mixture familiarity and then intensity. We found similar sensitivity to changes in odor mixtures regardless whether the modifying compound was added or subtracted, suggesting that perceptual stability of odor mixtures is equally dependent on both imputing missing information (pattern completion) and disregarding extraneous information. [ABSTRACT FROM AUTHOR]

An investigation to identify odorants responsible for a pleasant woody perfume‐like aroma produced in the fermentation broth of the fungus Daldinia childiae (JD Rogers & YM Ju) was conducted. Thirty odorants were identified from 30‐day‐old fermentations employing solvent‐assisted flavour evaporation (SAFE) and aroma extract dilution analysis (AEDA). Eleven odorants with flavour dilution (FD) factors ≥16 were quantitated using stable isotope dilution assays (SIDA), and odour activity values (OAV) determined. Odorants with the highest OAVs included guai‐11‐en‐10‐ol (woody, OAV 102689), 1‐octen‐3‐one (mushroom, OAV 9025), sotolon (maple, OAV 458), and (2E)‐non‐2‐enal (fatty, OAV 70). An odour simulation model formulated using odorants with OAV ≥ 1 closely matched the sensory attributes of natural D childiae fermentations. Guai‐11‐en‐10‐ol, a component of patchouli essential oil used widely in perfumery and cosmetics, was identified as the key impact odorant driving the pleasant woody perfume‐like aroma in D childiae fermentations. The findings from this investigation lay the groundwork for future studies on D childiae as a source for the sustainable biotechnological production of guai‐11‐en‐10‐ol with potential applications in the flavour and fragrance industry. [ABSTRACT FROM AUTHOR]

Importance: Cannabis use is consistently linked to poorer mental health outcomes, and there is evidence that use of higher-potency cannabis increases these risks. To date, no studies have described the association between cannabis potency and concurrent mental health in a general population sample or addressed confounding using longitudinal data.Objective: To explore the association between cannabis potency and substance use and mental health outcomes, accounting for preceding mental health and frequency of cannabis use.Design, Setting, and Participants: This cohort study used data from the Avon Longitudinal Study of Parents and Children, a UK birth cohort of participants born between April 1, 1991, and December 31, 1992. Present data on outcomes and exposures were collected between June 2015 and October 2017 from 1087 participants at 24 years of age who reported recent cannabis use.Exposures: Self-reported type of cannabis most commonly used in the past year, coded to a binary exposure of use of high-potency cannabis or lower-potency cannabis.Main Outcomes and Measures: Outcomes were reported frequency of cannabis use, reported cannabis use problems, recent use of other illicit drugs, tobacco dependence, alcohol use disorder, depression, generalized anxiety disorder, and psychotic-like experiences. The study used secondary data; consequently, the hypotheses were formulated after data collection.Results: Past-year cannabis use was reported by 1087 participants (580 women; mean [SD] age at onset of cannabis use, 16.7 [3.0] years). Of these, 141 participants (13.0%) reported the use of high-potency cannabis. Use of high-potency cannabis was associated with increased frequency of cannabis use (adjusted odds ratio [AOR], 4.38; 95% CI, 2.89-6.63), cannabis problems (AOR, 4.08; 95% CI, 1.41-11.81), and increased likelihood of anxiety disorder (AOR, 1.92; 95% CI, 1.11-3.32). Adjustment for frequency of cannabis use attenuated the association with psychotic experiences (AOR 1.29; 95% CI, 0.67-2.50), tobacco dependence (AOR, 1.42; 95% CI, 0.89-2.27), and other illicit drug use (AOR, 1.29; 95% CI, 0.77-2.17). There was no evidence of association between the use of high-potency cannabis and alcohol use disorder or depression.Conclusions and Relevance: To our knowledge, this study provides the first general population evidence suggesting that the use of high-potency cannabis is associated with mental health and addiction. Limiting the availability of high-potency cannabis may be associated with a reduction in the number of individuals who develop cannabis use disorders, the prevention of cannabis use from escalating to a regular behavior, and a reduction in the risk of mental health disorders. [ABSTRACT FROM AUTHOR]

Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (CICIL) methodology. Results from subgroup analyses comparing genetic mutations and TS metrics were assessed and applied to survival analyses. Data from four mCRC clinical studies were analyzed (1781 patients, 6369 iTLs). CICIL was used to assess differences in lesion TS dynamics within a tissue (intra-class) or across different tissues (inter-class). First, lesions were automatically classified based on their location. Cross-correlation coefficients (CCs) determined if each pair of lesions followed similar or opposite dynamics. Finally, CCs were grouped by using the K-means clustering method. Heterogeneity in tumor dynamics was lower in the intra-class analysis than in the inter-class analysis for patients receiving cetuximab. More tumor heterogeneity was found in KRAS mutated patients compared to KRAS wild-type (KRASwt) patients and when using sum of longest diameters versus sum of products of diameters. Tumor heterogeneity quantified as the median patient's CC was found to be a predictor of overall survival (OS) (HR = 1.44, 95% CI 1.08–1.92), especially in KRASwt patients. Intra- and inter-tumor tissue heterogeneities were assessed with CICIL. Derived metrics of heterogeneity were found to be a predictor of OS time. Considering differences between lesions' TS dynamics could improve oncology models in favor of a better prediction of OS. [ABSTRACT FROM AUTHOR]

The Internet and the way people use it are constantly changing. Knowing traffic is crucial for operating the network, understanding users’ needs, and ultimately improving applications. Here, we provide an in-depth longitudinal view of Internet traffic during 5 years (from 2013 to 2017). We take the point of the view of a national-wide ISP and analyze rich flow-level measurements to pinpoint and quantify changes. We observe the traffic, both from a point of view of users and services. We show that an ordinary broadband subscriber downloaded in 2017 more than twice as much as they used to do 5 years before. Bandwidth hungry video services drove this change at the beginning, while recently social messaging applications contribute to increase of data consumption. We study how protocols and service infrastructures evolve over time, highlighting events that may challenge traffic management policies. In the rush to bring servers closer and closer to users, we witness the birth of the sub-millisecond Internet, with caches located directly at ISP edges. The picture we take shows a lively Internet that always evolves and suddenly changes. To support new analyses, we make anonymized data available at https://smartdata.polito.it/five-years-at-the-edge/. [ABSTRACT FROM AUTHOR]

Pseudoreplication occurs when the number of measured values or data points exceeds the number of genuine replicates, and when the statistical analysis treats all data points as independent and thus fully contributing to the result. By artificially inflating the sample size, pseudoreplication contributes to irreproducibility, and it is a pervasive problem in biological research. In some fields, more than half of published experiments have pseudoreplication – making it one of the biggest threats to inferential validity. Researchers may be reluctant to use appropriate statistical methods if their hypothesis is about the pseudoreplicates and not the genuine replicates; for example, when an intervention is applied to pregnant female rodents (genuine replicates) but the hypothesis is about the effect on the multiple offspring (pseudoreplicates). We propose using a Bayesian predictive approach, which enables researchers to make valid inferences about biological entities of interest, even if they are pseudoreplicates, and show the benefits of this approach using two in vivo data sets. [ABSTRACT FROM AUTHOR]

To identify fruit processing treatments relevant for functional food applications, beverages prepared from processed Garcinia xanthochymus fruits were investigated. Treatments, including air drying (AD), sun drying (SD), freeze drying (FD), high and low temperature blanching (BH and BL), and high and low sulfating (SH and SL) were evaluated for their effects on sensory quality, pH, color, free-radical scavenging activity (DPPH), and anti-inflammatory activity. Sensory analysis concluded that the BH treatment had an elevated tropical-note as compared to the SD treatment, whereas the highest pH, b* value and DPPH scavenging activities were recorded for FD, BL, and BH treatments, respectively. Activity-guided fractionation of fruit extracts led to the identification of 2,4,6,3′,4′-pentahydroxybenzophenone-2-O-ß-D-glucopyranoside (1), showing an 80% reduction in IL-6 and a 31% reduction in nitric oxide (NO) levels. Quantitation of (1) revealed that FD followed by BH had the highest levels, at 24.9 mg/g and 2.3 mg/g, respectively. The results from this study demonstrated the potential of processed G. xanthochymus fruit as a functional beverage ingredient, with good sensory characteristics along with antioxidant and anti-inflammatory activities. This study examined the potential of processed G. xanthochymus fruit as the basis of a functional beverage. [ABSTRACT FROM AUTHOR]

Recent advances in transducer and computing technology have pushed the concept of continuous active sonar (CAS) or high duty cycle sonar as an area of interest for application to antisubmarine warfare. Unlike conventional pulsed active sonars, CAS processing aims at detecting echoes while transmitting with a nearly 100% duty cycle. This paper describes the signal processing chain developed at the Centre for Maritime Research and Experimentation (CMRE), La Spezia, Italy, for real-time CAS processing within an autonomous networked multistatic sonar system. The algorithm uses subband processing, which can potentially provide a higher target update rate than the traditional pulsed active sonar, while maintaining the same search radius. The higher rate of contact information can improve target tracking performance. Performance results are given from the COLLAB–NGAS14 sea trial where the CAS processor was deployed on two autonomous underwater vehicles (AUVs) acting as receivers of the CMRE experimental multistatic demonstrator. Results show the feasibility of the CAS concept in littoral scenarios, using AUVs as real-time receivers. [ABSTRACT FROM AUTHOR]

Aims: Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune‐mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: CLARITY was a 96‐week, double‐blind, placebo‐controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post‐dose ECGs. ECG data were collected 15 minutes pre‐dose and between 0.5 and 3 hours post‐dose at pre‐study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results: For cladribine tablets 3.5 mg/kg, the maximum change in placebo‐adjusted post‐dose QTcF vs. visit‐baseline (BL) was −0.42 ms (90% CI: −3.61–4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: −0.08–6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post‐dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53–11.44) and 8.74 ms (90% CI: 3.18–14.31), respectively. No significant changes were observed in T‐wave morphology in either treatment group. Conclusions: Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization. [ABSTRACT FROM AUTHOR]

Cladribine Tablets (MAVENCLAD®) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk. [ABSTRACT FROM AUTHOR]

Introduction: Cladribine Tablets (MAVENCLAD®) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4-5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3-4 lymphopenia, especially those patients with Grade ≥  2 lymphopenia at the start of year 2. Guidelines allowing treatment postponements during year 2 have been proposed for patients with a low ALC, subsequent to CLARITY, the pivotal clinical trial.Methods: A virtual population was generated using characteristics from CLARITY patients. A clinical trial simulation was performed to determine the impact of alternative treatment scenarios on ALC and relapse rate, by postponing treatment in year 2 to allow for longer ALC recovery time in patients who required it. Should a patient not recover to normal ALC (Grade 0) or Grade 1 lymphopenia within the period defined in the treatment algorithm, treatment in year 2 was suspended.Results: Results were similar across considered scenarios, which implemented different postponement durations. Specifically, ~  92% of virtual subjects did not require treatment postponement and <  1% discontinued due to Grade 2-4 lymphopenia at the end of the maximally permitted postponement. Less severe lymphopenia was observed during year 2 when a treatment algorithm was applied. The effect on relapse rate over 2 years was negligible.Conclusions: Results support treatment guidelines to decrease the risk of severe lymphopenia following treatment with Cladribine Tablets, while preserving efficacy.Trial Registration: CLARITY; ClinicalTrials.gov: NCT00213135. [ABSTRACT FROM AUTHOR]

Background and aims: Using smoking cessation medications for several weeks prior to quitting smoking facilitates quitting success, but how it does so is not clear. Candidate theories are that pre‐cessation medication enhances self‐efficacy, facilitates medication adherence post‐quit, induces aversion to smoking, reduces reward from smoking or reduces the drive to smoke. We investigated these pathways using data from a large trial of nicotine pre‐loading, using mediation analysis. Design Randomized controlled trial of nicotine pre‐loading. Potential mediators were assessed at baseline and 1 week into the pre‐loading (3 weeks prior to quitting). In addition to this, urges to smoke in abstainers were assessed 1 week after the target quit date. Setting England. Participants: A total of 1792 smokers who wanted to quit attending specialist smoking cessation services in England were enrolled between 13 August 2012 and 10 March 2015. Intervention and comparator: Participants were randomized to either standard smoking cessation medications accompanied by behavioural support or the same treatment supplemented by nicotine 'pre‐loading', i.e. 4 weeks of 21 mg nicotine patch use prior to quitting. Measurements The primary outcome, selected for its proximity in time to potential mediators, was biochemically validated abstinence from smoking at 4 weeks post‐target quit date. Potential mediators included the Modified Cigarette Evaluation Questionnaire, with subscales assessing satisfaction, reward, craving and aversion; ratings of strength and frequency of urges to smoke; the Mood and Physical Symptoms Scale assessing cigarette withdrawal symptoms; two items from the Nicotine Dependence Syndrome Scale assessing smoking stereotypy; self‐reported reduction in cigarettes per day and in carbon monoxide (CO) reading; post‐target quit day (TQD) medication adherence; self‐efficacy; nausea. Findings Pre‐loading reduced urges to smoke at 3 weeks pre‐quit (P < 0.001) and exhaled CO concentrations (P < 0.001), and also urges to smoke post‐quit in abstainers (P = 0.001). At 3 weeks pre‐quit, it also reduced cigarette consumption, enjoyment of and satisfaction from smoking and smoking reward and increased nausea, aversion (all P < 0.001) and smoking stereotypy (P = 0.003). Only the first three variables, however (reduced smoke intake and reduced urges to smoke pre‐ and post‐quit), mediated abstinence from smoking at 4 weeks and only the latter two mediated abstinence at 6 months (indirect mediating effects P < 0.05). Conclusions: Nicotine pre‐loading appears to facilitate smoking abstinence by reducing urges to smoke and smoke intake before quitting and urges to smoke after quitting. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting‐relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC‐related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit‐linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC‐derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism‐specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market. [ABSTRACT FROM AUTHOR]

Abstract: Lily bulbs (Lilium longiflorum Thunb.), known as ‘Bai He’ in Chinese, are a popular ingredient used in Asian cooking. Despite their popularity, little is known about the odorants responsible for their distinct aroma. The key aroma‐active compounds present in both raw and roasted lily bulbs were isolated by solvent extraction followed by solvent‐assisted flavour evaporation (SAFE) and gas chromatography–olfactometery (GC/O) analysis. A comparative aroma extract dilution analysis (cAEDA) in the flavour dilution (FD) factor range from ≥1 to 1024 resulted in 48 aroma‐active compounds reported in L. longiflorum bulbs for the first time. The highest FD factors in raw lily bulbs were determined for (E)‐hex‐3‐enal (green, FD 1024) and 3‐methylsulfanylpropanal (cooked potato‐like, FD 1024), followed by 2,2,4‐trimethyl‐3‐oxabicyclo[2.2.2]octane (eucalyptus‐like, FD 256) and 2‐phenyl acetaldehyde (floral, FD 256). Following roasting, odorants with high FD values in raw lily bulbs decreased in intensity. The thermal treatment resulted in the generation of 34 aroma‐active compounds. Aroma‐active compounds with FD factors of ≥1024 in roasted lily bulbs were identified as 1‐(3,4‐dihydro‐2H‐pyrrol‐5‐yl)ethan‐1‐one (roasty), 3‐methylsulfanylpropanal (cooked potato‐like), 2‐ethyl‐3,5‐dimethylpyrazine (earthy), 2,3‐diethyl‐5‐methylpyrazine (earthy), 3‐hydroxy‐4,5‐dimethyl‐2(5H)‐furanone (maple‐like), 2‐ethyl‐4‐hydroxy‐3‐methyl‐2H‐furan‐5‐one (maple‐like), and 2‐methoxy‐4‐[(E)‐prop‐1‐enyl]phenol (clove‐like). In summary, the aroma‐active compounds with high FD factors in raw lily bulbs decreased significantly as a result of roasting, and a new pool of aroma‐active compounds were formed during the roasting process. [ABSTRACT FROM AUTHOR]

The considerable thicknesses of common insulation systems, applied to the internal or external building envelope, can be inappropriate in the Mediterranean climates for improving buildings' energy efficiency and their internal comfort at the same time; in fact, the high thicknesses of insulating material provided by legislation standards can be cause of environments' over-heating and formation of condensation. In this framework, the S-MUnSTa system is an innovative dynamic ventilated insulation system able to overcome condensation and overheating phenomena, also exploiting Internet of Things technologies; the main characteristic of the proposed smart insulation is that the ventilated external layer is equipped with dynamic valves of insulating material, for opening and closing the air channel, with the aim to optimize the thermal performance. In order to guarantee the expected performance of the system, as it has been patented, in this paper an innovative fixing system to install the insulating panels is presented. This new method allows a rapid and easy installation, without any specialization required and with low maintenance costs. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy. [ABSTRACT FROM AUTHOR]

Mathematical models of tumor dynamics generally omit information on individual target lesions (iTLs), and consider the most important variable to be the sum of tumor sizes (TS). However, differences in lesion dynamics might be predictive of tumor progression. To exploit this information, we have developed a novel and flexible approach for the non‐parametric analysis of iTLs, which integrates knowledge from signal processing and machine learning. We called this new methodology ClassIfication Clustering of Individual Lesions (CICIL). We used CICIL to assess similarities among the TS dynamics of 3,223 iTLs measured in 1,056 patients with metastatic colorectal cancer treated with cetuximab combined with irinotecan, in two phase II studies. We mainly observed similar dynamics among lesions within the same tumor site classification. In contrast, lesions in anatomic locations with different features showed different dynamics in about 35% of patients. The CICIL methodology has also been implemented in a user‐friendly and efficient Java‐based framework. [ABSTRACT FROM AUTHOR]

This paper presents a data-driven approach to control the movement of autonomous underwater vehicles (AUVs) operating as receivers of a multistatic sonar surveillance network. The algorithm adopts a nonmyopic receding horizon policy to control the AUV heading, with the objective of minimizing the expected estimate error in the target location produced by the onboard tracker. Minimizing this error is of the utmost interest in target state estimation since it is one way of maintaining tracks. The proposed policy builds on an automated perception module which produces a target track and on an acoustic model to estimate the target measurement signal-to-noise ratio. Driven by the mission objectives, it explores the best decisions for the AUV by evaluating the evolution of the tactical situation over a future time window. Nonmyopic approaches can offer increased performance if compared to myopic ones. The downside is an increase of the computational burden. Methods are described to simplify and solve effectively the resulting decision tree to allow the execution of these kinds of computational intensive algorithms onboard autonomous vehicles. At the same time, they aim at producing AUV paths robust to possible misleading target measurements, which might cause meandering trajectories. These are crucial factors to use data-driven strategies for AUVs which must work in real applications. Results from the COLLAB13 sea trial are reported and discussed. They show both the feasibility of executing the algorithm in realtime on an onboard computer and the benefits of using the proposed approach over conventional predefined paths. These results are, to the best of our knowledge, the first successful demonstration at sea of a complex nonmyopic algorithm running in realtime onboard AUVs in a realistic multistatic littoral surveillance scenario. [ABSTRACT FROM AUTHOR]

Case: Following an insidious onset of symptoms, a 29-year-old man who had no risk factors for tuberculosis was diagnosed with tuberculosis of the iliac crest. The red flag in this case was the patient's progressive deterioration despite a variety of antibiotic regimens. Histopathologic demonstration of necrotic granulomatous inflammation and a positive culture led to the diagnosis. A combination of surgery and antitubercular-drug therapy resulted in clinical recovery. Conclusion: Iliac crest tuberculosis represents <1% of all skeletal tuberculosis cases. Even in the absence of classic symptoms and risk factors, orthopaedic surgeons shouldmaintain a low threshold for tuberculosis in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.Methods: This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.Results: The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance.Conclusions: Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135. [ABSTRACT FROM AUTHOR]

Purpose: This study is to examine how viewing a Japanese garden affects Japanese patients with dementia. Background: In a previous study, authors explored the effect on individuals with Alzheimer’s disease of viewing an indoor Japanese garden at a nursing home in the United States and reported that viewing the garden significantly reduced the heart rate, evoked short-term and long-term memories, and improved behavioral symptoms. However, it was unclear whether these effects were caused by the design of Japanese garden or unfamiliarity of the design to Caucasians. Methods: We constructed a Japanese garden on the rooftop of a hospital in Japan and assessed with a total of 25 subjects on the following categories: (1) eye movement, (2) heart rate, and (3) behavior under four different conditions: (a) open view of the site before construction of the Japanese garden (the control space), (b) open view of the Japanese garden, (c) view of the Japanese garden through closed door, and (d) view of Japanese garden through closed door with the chrysanthemum scent. Findings/Results: Viewers’ eyes scanned larger area while viewing the Japanese garden, and viewing the Japanese garden significantly reduced heart rate and improved behavioral symptoms than the control space. We also found that the effect of viewing the same Japanese garden differed across three conditions: the view through an open door, a closed door, and a closed door with added scent. [ABSTRACT FROM AUTHOR]

Anecdotal reports suggest that motion sickness may occur among users of contemporary, consumer-oriented head-mounted display systems and that women may be at greater risk. We evaluated the nauseogenic properties of one such system, the Oculus Rift. The head-mounted unit included motion sensors that were sensitive to users' head movements, such that head movements could be used as control inputs to the device. In two experiments, seated participants played one of two virtual reality games for up to 15 min. In Experiment 1, 22% of participants reported motion sickness, and the difference in incidence between men and women was not significant. In Experiment 2, motion sickness was reported by 56% of participants, and incidence among women (77.78%) was significantly greater than among men (33.33%). Before participants were exposed to the head-mounted display system, we recorded their standing body sway during the performance of simple visual tasks. In both experiments, patterns of pre-exposure body sway differed between participants who (later) reported motion sickness and those who did not. In Experiment 2, sex differences in susceptibility to motion sickness were preceded by sex differences in body sway. These postural effects confirm a prediction of the postural instability theory of motion sickness. The results indicate that users of contemporary head-mounted display systems are at significant risk of motion sickness and that in relation to motion sickness these systems may be sexist in their effects. [ABSTRACT FROM AUTHOR]

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.Results: In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria.Trial Registration: ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011. [ABSTRACT FROM AUTHOR]