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Background The hollow-fibre system model of tuberculosis (HFS-TB) has been endorsed by regulators; however, application of HFS-TB requires a thorough understanding of intra- and inter-team variability, statistical power and quality controls. Methods Three teams evaluated regimens matching those in the Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) study, plus two high-dose rifampicin/pyrazinamide/moxifloxacin regimens, administered daily for up to 28 or 56 days against Mycobacterium tuberculosis (Mtb) under log-phase growth, intracellular growth or semidormant growth under acidic conditions. Target inoculum and pharmacokinetic parameters were pre-specified, and the accuracy and bias at achieving these calculated using percent coefficient of variation (%CV) at each sampling point and two-way analysis of variance (ANOVA). Results A total of 10 530 individual drug concentrations, and 1026 individual cfu counts were measured. The accuracy in achieving intended inoculum was >98%, and >88% for pharmacokinetic exposures. The 95% CI for the bias crossed zero in all cases. ANOVA revealed that the team effect accounted for 20% difference in slope, with a power of >99%. Conclusions HFS-TB is a highly tractable tool for choosing combination regimens with little variability between teams, and between replicates.

To revisit the independent importance of ciliary body involvement (CBI), monosomy 3 (M3), tumour size, histological and clinical factors in uveal melanoma (UM) and to devise a new prognostic classification based on a combination of the American Joint Committee on Cancer (AJCC) and the Cancer Genome Atlas (TCGA) models.Two cohorts with a total of 1796 patients were included. Clinicopathological factors were compared between patients with and without CBI and M3. Development of the prognostic classification was performed in a training cohort and was then tested in two independent validation cohorts.Tumours with CBI were more common in women, had greater apical thickness, greater basal tumour diameter, greater rates of vasculogenic mimicry and greater rates of M3, were more often asymptomatic at diagnosis and had poorer 5- and 10-year globe conservation rates (p 0.023). In multivariate logistic regression, patient age at diagnosis, tumour diameter and CBI were independent predictors of M3 (p 0.001). In multivariate Cox regression, male sex, age at diagnosis, tumour diameter, M3 and CBI were independent predictors of metastasis. The proposed prognostic classification combined patient age, sex, CBI, extraocular extension, M3, 8q (optional) and tumour size, and demonstrated greater prognostic acumen than both AJCC 4 T categories and TCGA groups A to D in validation cohorts.Tumour size does not confound the prognostic implication of CBI, M3, male sex and age at diagnosis in UM. These factors were included in a new prognostic classification that outperforms AJCC T category and TCGA groups.

Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically‐based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N‐desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty‐four percent (area under the curve [AUC]) and 91% (maximum concentration [C max]) of simulated mean values were within 1.5‐fold of the observed data and the simulated drug‐drug interaction ratios were within 1.5‐fold (AUC) and twofold (C max) of the observed data for nine (AUC) and eight (C max) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients’ with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th–95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fumass), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within‐subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open‐source to aid further research.

Background Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681)

Wittgenstein and the Concepts of Mind in Hegel. Hegel distinguishes three main forms of the (subjective) mind – the soul, the consciousness and the spirit. He seeks to use these concepts to rediscover the meaning of Aristotle’s works on the soul (Περὶ ψυχῆς) and, at the same time, to counteract certain scientistic tendencies within the philosophy of mind. Although Wittgenstein (most likely) was not aware of these Hegelian distinctions, his own use of the concepts of mind exhibits some remarkable similarities to Hegel’s, and Wittgenstein too develops his understanding of mind by first examining the scientific psychology of his time and delineating his own position by way of contrast with it.This article examines three areas in which Wittgenstein substantially developed his understanding of the concepts of mind. The sequence of the investigation follows the order in which these areas became significant for Wittgenstein’s thinking, and compares them in each case with the three main Hegelian forms of the concepts of mind.

Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease-related cause of death worldwide, necessitating the development of new and improved treatment regimens. Nonclinical evaluation of candidate drug combinations via the relapsing mouse model (RMM) is an important step in regimen development, through which candidate regimens that provide the greatest decrease in the probability of relapse following treatment in mice may be identified for further development. Although RMM studies are a critical tool to evaluate regimen efficacy, making comprehensive "apples to apples" comparisons of regimen performance in the RMM has been a challenge in large part due to the need to evaluate and adjust for variability across studies arising from differences in design and execution. To address this knowledge gap, we performed a model-based meta-analysis on data for 17 unique regimens obtained from a total of 1592 mice across 28 RMM studies. Specifically, a mixed-effects logistic regression model was developed that described the treatment duration- dependent probability of relapse for each regimen and identified relevant covariates contributing to interstudy variability. Using the model, covariate-normalized metrics of interest, namely, treatment duration required to reach 50% and 10% relapse probability, were derived and used to compare relative regimen performance. Overall, the model-based meta-analysis approach presented herein enabled cross-study comparison of efficacy in the RMM and provided a framework whereby data from emerging studies may be analyzed in the context of historical data to aid in selecting candidate drug combinations for clinical evaluation as TB drug regimens.

Denne masteroppgaven er basert på fire musikklæreres utsagn om hvordan de oppfatter at bruk av iPad bidrar til å heve kvaliteten på sine elevers arbeidsprosess og produkter når de skal lage musikk. Det fokuseres både på positive og negative aspekter ved dette. Informantene er norske lærere på ulike barneskoler i Bærum. Hovedproblemstillingen i denne masteroppgaven er: Hvordan oppfatter musikklærere at bruk av digitale verktøy kan virke hemmende eller fremmende for elevers arbeid med komponering på barneskolen, sammenlignet med tradisjonelle musikkinstrumenter? I læreplanen (LK20) for musikkfaget er digitale ferdigheter og det å lage musikk to viktige elementer. Data fra studien viser at lærerne mener det er mange gode grunner til at vi må bruke de digitale ressursene skolen har tilgjengelig når elever skal komponere og improvisere. Disse funnene støttes av tidligere forskning på digital komponering i skolen. Lærerne mener også at det er viktig å ta vare på tradisjonen med akustiske instrumenter og lydkilder, og kan med fordel kombineres med de mange lydene som finnes på iPaden, i GarageBand spesielt. This master's thesis is based on statements from four music teachers of how they perceive the use of iPad helps to raise the quality of their students' work process and musical products when they make music in school. It focuses on both positive and negative aspects of this. The informants are Norwegian teachers at various primary schools in Bærum. The main research question in this master's thesis is: How do music teachers perceive that the use of digital tools can have an inhibiting or promoting effect on students' engagement in composition in primary school, in relation to traditional musical instruments? In the Norwegian curriculum (LK20) for music, digital skills and making music are two important elements. Data in the study shows that the teachers believe there are many good reasons why we must use the digital resources at the school when students compose and improvise music. These findings are supported by previous research on digital composition in schools. The teachers also believe that it is important to hold on to the tradition of acoustic instruments and sound sources, and can be combined with the many sounds found on the iPad, in GarageBand in particular.

Key features • COVIDMENT [www.covidment.is] is a NordForsk-funded research collaboration across six nations, with the overarching aim to significantly advance current knowledge on mental morbidity trajectories associated with the coronavirus disease 2019 (COVID-19) in the general population and in specific risk groups. • From March 2020 through August 2021, 392 817 individuals have been recruited to the seven COVIDMENT cohorts: the Danish Blood Donor Study (N ¼ 71 562), the Estonian Biobank COVID-19 and Mental Health Data Collection cohorts (N ¼ 13 329 and N ¼ 86 116, respectively), the Icelandic COVID-19 National Resilience Cohort (N ¼ 22 849), the Norwegian BRY.DEG2020 (N ¼ 19 343), the Norwegian Mother, Father and Child Cohort Study (N ¼ 132 486), the Scottish Generation Scotland/CovidLife (N ¼ 18 518) and the Swedish Omtanke2020 (N ¼ 28 614). Semi-harmonized questionnaire data have been collected across all COVIDMENT cohorts with longitudinal data available, e.g. through linkage to the national registers. • The average age of participants ranged from 31.8 to 58.5 years across cohorts. The prevalence of depressive symptoms above cut-off point varied considerably across cohorts (4.2–20.8%). The prevalence of depressive symptoms was highest at COVID-19 incidence of 30 cases per week per 100 000 persons, i.e. 14.3% [95% confidence interval (CI): 9.4–21.8%], which was 61.0% (95% CI: 34.0–94.1%) higher than the prevalence at COVID-19 incidence of 0 cases per week per 100 000 persons (P ¼ 1.1 x 10 ^( 6)). •

Photoinduced electron transfer systems can mimic certain features of natural photosynthetic reaction centers, which are crucial for solar energy production. Among other tetra-pyrroles, the versatile chemical and photophysical properties of corroles make them very promising donors applicable in donor–acceptor complexes. Here, we present a first comprehensive study of ultrafast photoinduced electron transfer in a self-assembling sulfonated aluminum corrole–methylviologen complex combining visible and mid-IR transient absorption spectroscopy. The noncovalent D–A association of the corrole–methylviologen complex has the great advantage that photoinduced charge separation becomes possible even though the back electron transfer (BET) rate is large. Initial forward electron transfer from corrole to methylviologen is observed on an ∼130 fs time scale. Subsequent back electron transfer takes place with τBET = (1.8 ± 0.5) ps, revealing very complex relaxation dynamics. Direct probing in the mid-IR allows us to unravel the back electron transfer and cooling dynamics/electronic reorganization. Upon tracing the dynamics of the methylviologen-radical marker band at 1640 cm–1 and the C═C stretching of corrole at around 1500 cm–1, we observe that large amounts of excess energy survive the back transfer, leading to the formation of hot ground state absorption. A closer examination of the signal after 300 ps, surviving the back transfer, exhibits a charge-separation yield of 10–15%.

ObjectivesAnimal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3–4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB).MethodsA series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen.ResultsUsing linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13–0.23) versus 0.15 (95% credible interval=0.08–0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13–0.18) versus 0.11 (95% credible interval=0.09–0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1–41.34) and 72.30% (95% credible interval=71.41–73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18–94.13) at 6 months for standard therapy.ConclusionsThe kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.

The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.

The wasp family Chrysididae (cuckoo wasps, gold wasps) comprises exclusively parasitoid and kleptoparasitic species, many of which feature a stunning iridescent coloration and phenotypic adaptations to their parasitic life style. Previous attempts to infer phylogenetic relationships among the family’s major lineages (subfamilies, tribes, genera) based on Sanger sequence data were insufficient to statistically resolve the monophyly and the phylogenetic position of the subfamily Amiseginae and the phylogenetic relationships among the tribes Allocoeliini, Chrysidini, Elampini, and Parnopini (Chrysidinae). Here, we present a phylogeny inferred from nucleotide sequence data of 492 nuclear single-copy genes (230,915 aligned amino acid sites) from 94 species of Chrysidoidea (representing Bethylidae, Chrysididae, Dryinidae, Plumariidae) and 45 outgroup species by combining RNA-seq and DNA target enrichment data. We find support for Amiseginae being more closely related to Cleptinae than to Chrysidinae. Furthermore, we find strong support for Allocoeliini being the sister lineage of all remaining Chrysidinae, whereas Elampini represent the sister lineage of Chrysidini and Parnopini. Our study corroborates results from a recent phylogenomic investigation, which revealed Chrysidoidea as likely paraphyletic.

Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic therapeutic strategies have been unsuccessful to date and radiotherapy (RT) remains the standard of care. A central impediment to systemic therapy is the blood-brain barrier (BBB), which precludes drug delivery to the tumor site. Focused ultrasound (FUS) with intravenous microbubbles can transiently and non-invasively circumvent the BBB to enhance drug delivery. Nevertheless, it remains unclear whether FUS is safe at the brainstem in combination with clinical doses of RT. In this study, we hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. To establish a safety timeline, we administered FUS to the brainstem of nontumor bearing mice concurrent with or adjuvant to radiation; then, we validated our findings in a syngeneic orthotopic xenograft DMG model which received repeated sonication concurrent with RT. Male B6 (Cg)-Tyrc-2J/J albino mice received intracranial injection of 4423 mouse DMG cells (PDGFB+, H3.3K27M, p53−/−) at a location posterior and lateral to the lambda. A clinical RT dose of 39 Gy in 13 fractions was delivered to the brainstem with the Small Animal Radiation Research Platform (SARRP) or the XRAD-320 irradiator. FUS was administered with a 0.5 MHz transducer, and both BBBO and tumor volume were monitored with MRI. FUS-mediated BBBO in nontumor bearing mice receiving RT did not affect cardiorespiratory rate, motor function, and tissue integrity. Moreover, tumor bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy over 13 fractions offered local control, although disease progression occurred in all animals approximately 3-4 weeks post-RT. Ultimately, repeated FUS-mediated BBB opening concurrent with RT is safe and feasible. In our brainstem DMG model, relapse occurs, making it ideal for future tests of combinatorial RT and FUS-mediated drug delivery.

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0–24/MIC), with a PDT of 252., Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0–24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0–24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0–24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0–24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia’s formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.