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Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000–2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57–58%) for Danish-born patients, 57% (55–60%) for Western, and 56% (53–58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5–2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13–1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of anal squamous cell carcinoma (ASCC) is increasing worldwide, with a significant proportion of patients treated with curative intent having recurrence. The ability to accurately predict progression-free survival (PFS) and overall survival (OS) would allow for development of personalised treatment strategies. The aim of the study was to train and external test radiomic/clinical feature derived time-to-event prediction models. Methods: Consecutive patients with ASCC treated with curative intent at two large tertiary referral centres with baseline FDG PET-CT were included. Radiomic feature extraction was performed using LIFEx software on the pre-treatment PET-CT. Two distinct predictive models for PFS and OS were trained and tuned at each of the centres, with the best performing models externally tested on the other centres' patient cohort. Results: A total of 187 patients were included from centre 1 (mean age 61.6 ± 11.5 years, median follow up 30 months, PFS events = 57/187, OS events = 46/187) and 257 patients were included from centre 2 (mean age 62.6 ± 12.3 years, median follow up 35 months, PFS events = 70/257, OS events = 54/257). The best performing model for PFS and OS was achieved using a Cox regression model based on age and metabolic tumour volume (MTV) with a training c-index of 0.7 and an external testing c-index of 0.7 (standard error = 0.4). Conclusions: A combination of patient age and MTV has been demonstrated using external validation to have the potential to predict OS and PFS in ASCC patients. Clinical relevance statement: A Cox regression model using patients' age and metabolic tumour volume showed good predictive potential for progression-free survival in external testing. The benefits of a previous radiomics model published by our group could not be confirmed on external testing. Key Points: • A predictive model based on patient age and metabolic tumour volume showed potential to predict overall survival and progression-free survival and was validated on an external test cohort. • The methodology used to create a predictive model from age and metabolic tumour volume was repeatable using external cohort data. • The predictive ability of positron emission tomography-computed tomography–derived radiomic features diminished when the influence of metabolic tumour volume was accounted for. [ABSTRACT FROM AUTHOR]

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors. [ABSTRACT FROM AUTHOR]

Currently, the International Prognostic Index (IPI) is the most used and reported model for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). IPI-like variations have been proposed, but only a few have been validated in different populations (e.g., revised IPI (R-IPI), National Comprehensive Cancer Network IPI (NCCN-IPI)). We aimed to validate and compare different IPI-like variations to identify the model with the highest predictive accuracy for survival in newly diagnosed DLBCL patients. We included 5126 DLBCL patients treated with immunochemotherapy with available data required by 13 different prognostic models. All models could predict survival, but NCCN-IPI consistently provided high levels of accuracy. Moreover, we found similar 5-year overall survivals in the high-risk group (33.4%) compared to the original validation study of NCCN-IPI. Additionally, only one model incorporating albumin performed similarly well but did not outperform NCCN-IPI regarding discrimination (c-index 0.693). Poor fit, discrimination, and calibration were observed in models with only three risk groups and without age as a risk factor. In this extensive retrospective registry-based study comparing 13 prognostic models, we suggest that NCCN-IPI should be reported as the reference model along with IPI in newly diagnosed DLBCL patients until more accurate validated prognostic models for DLBCL become available. [ABSTRACT FROM AUTHOR]

Over the past decade, there has been a rapid increase in applications of multibody system dynamics to the predictive simulation of human movement. Using predictive "what-if" human dynamic simulations that do not rely on experimental testing or prototypes, new medical interventions and devices can be developed more quickly, cheaply, and safely. In this paper, we provide a comprehensive review of research into the predictive multibody dynamic simulation of human movements, with applications in clinical practice, medical and assistive device design, sports, and industrial ergonomics. Multibody models of human neuromusculoskeletal systems are reviewed, including models of joints, contacts, and muscle forces or torques, followed by a review of simulation approaches that use optimal control methods and a cost function to predict human movements. Modelling and optimal control software are also reviewed, and directions for future research are suggested. [ABSTRACT FROM AUTHOR]

To optimally adjust our behavior to changing environments we need to both adjust the speed of our decisions and movements. Yet little is known about the extent to which these processes are controlled by common or separate mechanisms. Furthermore, while previous evidence from computational models and empirical studies suggests that the basal ganglia play an important role during adjustments of decision-making, it remains unclear how this is implemented. Leveraging the opportunity to directly access the subthalamic nucleus of the basal ganglia in humans undergoing deep brain stimulation surgery, we here combine invasive electrophysiological recordings, electrical stimulation and computational modelling of perceptual decision-making. We demonstrate that, while similarities between subthalamic control of decision- and movement speed exist, the causal contribution of the subthalamic nucleus to these processes can be disentangled. Our results show that the basal ganglia independently control the speed of decisions and movement for each hemisphere during adaptive behavior. The neural mechanisms determining the speed of decisions and movements in the human brain remain poorly understood. Here, the authors reveal that the subthalamic nucleus causally controls decision and movement speed independently for each hemisphere. [ABSTRACT FROM AUTHOR]

Following its foundation in the 630s CE, medieval Basra rapidly expanded to became one of the most populous cities of southern Iraq and the wider Gulf region. At its foundation, the city's surrounding environment appears to have been poorly suited to sustaining a large urban population. This paper examines the different ways in which the early Islamic population of Basra transformed the immediate environs of the city to improve the urban water supply and the agricultural potential of the city's hinterland. In particular, this included the construction of substantial canals connecting Basra with sources of water such as the marshes to the north of the city and the Shaṭṭ al-cArab—the river which forms at the confluence of the Tigris and Euphrates and flows past Basra to the Gulf. The tidal influence of the Gulf causes the water level of the Shaṭṭ al-cArab to rise and fall daily and, by exploiting this characteristic, the medieval population of Basra could irrigate large swathes of land surrounding the city. Analysis of historic satellite imagery reveals possible evidence for the infrastructure that made this possible—including the remains of field systems bounded by, and interspersed with, canals as well as large raised linear ridge features which occur in tandem with relict canal systems. This paper critically assesses the evidence for the dating of these features, potential scenarios for how they functioned and their relationship to the medieval city of Basra. [ABSTRACT FROM AUTHOR]

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN. The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II. [ABSTRACT FROM AUTHOR]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R2-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2–82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP. [ABSTRACT FROM AUTHOR]

The advent of 'conservation agriculture' (CA) farming using zero- or no-tillage practices and an accompanying change in crop rotations in the last 10–15 years has potentially led to less disturbance of mouse burrows and increased cover and food supply. Given the irregular outbreaks of mice in grain cropping regions in Australia and the damage they cause, it is important to understand when and where mouse populations increase so that management strategies can be improved. We utilised a 20-year long-term mouse population data set collected prior to the introduction of CA farming practices and a more recent 8-year data set after CA to compare changes in mouse population abundance in a typical dryland grain cropping system in north-western Victoria, Australia. Mouse trapping data were used to compare abundance in crop and margin habitats during crop growth and non-crop (fallow) periods before ('conventional') and after introduction of CA. Mice are now resident year-round within crops and stubble and appear to only spill over into margin habitats. Previously developed recommendations for mouse management that include their control while in margin habitats may no longer be valid. [ABSTRACT FROM AUTHOR]

Essential tremor is a common neurological disorder, characterised by involuntary shaking of a limb. Patients are usually treated using medications which have limited effects on tremor and may cause side-effects. Surgical therapies are effective in reducing essential tremor, however, the invasive nature of these therapies together with the high cost, greatly limit the number of patients benefiting from them. Non-invasive therapies have gained increasing traction to meet this clinical need. Here, we test a non-invasive and closed-loop electrical stimulation paradigm which tracks peripheral tremor and targets thalamic afferents to modulate the central oscillators underlying tremor. To this end, 9 patients had electrical stimulation delivered to the median nerve locked to different phases of tremor. Peripheral stimulation induced a subtle but significant modulation in five out of nine patients—this modulation consisted mainly of amplification rather than suppression of tremor amplitude. Modulatory effects of stimulation were more pronounced when patient's tremor was spontaneously weaker at stimulation onset, when significant modulation became more frequent amongst subjects. This data suggests that for selected individuals, a more sophisticated control policy entailing an online estimate of both tremor phase and amplitude, should be considered in further explorations of the treatment potential of tremor phase-locked peripheral stimulation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with 'hyperdirect pathway' fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD. In Parkinson's disease (PD), beta frequency oscillations are synchronised across the cortico-basal-ganglia circuit. The authors show in human participants that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway, indicating a pathophysiological role for this pathway in PD. [ABSTRACT FROM AUTHOR]

The rates of quantum cryptographic protocols are usually expressed in terms of a conditional entropy minimized over a certain set of quantum states. In particular, in the device-independent setting, the minimization is over all the quantum states jointly held by the adversary and the parties that are consistent with the statistics that are seen by the parties. Here, we introduce a method to approximate such entropic quantities. Applied to the setting of device-independent randomness generation and quantum key distribution, we obtain improvements on protocol rates in various settings. In particular, we find new upper bounds on the minimal global detection efficiency required to perform device-independent quantum key distribution without additional preprocessing. Furthermore, we show that our construction can be readily combined with the entropy accumulation theorem in order to establish full finite-key security proofs for these protocols. Simple lower bounds on the rates of device-independent quantum information protocols can often overestimate the power of the eavesdropping party. Here, the authors use new entropic quantities defined as semidefinite programs to improve bounds in several regimes without expensive computational resources [ABSTRACT FROM AUTHOR]

Purpose: There is little evidence of the ergogenic effect of flow-resistive masks worn during exercise. We compared a flow-resistive face mask (MASK) worn during high-intensity interval training (HIIT) against pressure threshold loading inspiratory muscle training (IMT). Methods: 23 participants (13 males) completed a 5 km time trial and six weeks of HIIT (3 sessions weekly). HIIT (n = 8) consisted of repeated work (2 min) at the speed equivalent to 95% V ˙ O2 peak with equal rest. Repetitions were incremental (six in weeks 1, 2 and 6, eight in weeks 3 and 4 and ten in week 5). Participants were allocated to one of three training groups. MASK (n = 8) wore a flow-resistive mask during all sessions. The IMT group (n = 8) completed 2 × 30 breaths daily at 50% maximum inspiratory pressure (PImax). A control group (CON, n = 7) completed HIIT only. Following HIIT, participants completed two 5 km time trials, the first matched identically to pre-intervention trial (ISO time), and a self-paced effort. Results: Time trial performance was improved in all groups (MASK 3.1 ± 1.7%, IMT, 5.7 ± 1.5% and CON 2.6 ± 1.0%, p < 0.05). IMT improved greater than MASK and CON (p = 0.004). Post intervention, PImax and diaphragm thickness were improved in IMT only (32% and 9.5%, respectively, p = 0.003 and 0.024). Conclusion: A flow-resistive mask worn during HIIT provides no benefit to 5 km performance when compared to HIIT only. Supplementing HIIT with IMT improves respiratory muscle strength, morphology and performance greater than HIIT alone. [ABSTRACT FROM AUTHOR]

Objectives: To develop a breast cancer risk model to identify women at mammographic screening who are at higher risk of breast cancer within the general screening population. Methods: This retrospective nested case-control study used data from a population-based breast screening program (2009–2015). All women aged 40–75 diagnosed with screen-detected or interval breast cancer (n = 1882) were frequency-matched 3:1 on age and screen-year with women without screen-detected breast cancer (n = 5888). Image-derived risk factors from the screening mammogram (percent mammographic density [PMD], breast volume, age) were combined with core biopsy history, first-degree family history, and other clinical risk factors in risk models. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). Classifiers assigning women to low- versus high-risk deciles were derived from risk models. Agreement between classifiers was assessed using a weighted kappa. Results: The AUC was 0.597 for a risk model including only image-derived risk factors. The successive addition of core biopsy and family history significantly improved performance (AUC = 0.660, p < 0.001 and AUC = 0.664, p = 0.04, respectively). Adding the three remaining risk factors did not further improve performance (AUC = 0.665, p = 0.45). There was almost perfect agreement (kappa = 0.97) between risk assessments based on a classifier derived from image-derived risk factors, core biopsy, and family history compared with those derived from a model including all available risk factors. Conclusions: Women in the general screening population can be risk-stratified at time of screen using a simple model based on age, PMD, breast volume, and biopsy and family history. Key Points: • A breast cancer risk model based on three image-derived risk factors as well as core biopsy and first-degree family history can provide current risk estimates at time of screen. • Risk estimates generated from a combination of image-derived risk factors, core biopsy history, and first-degree family history may be more valid than risk estimates that rely on extensive self-reported risk factors. • A simple breast cancer risk model can avoid extensive clinical risk factor data collection. [ABSTRACT FROM AUTHOR]

MicroRNAs are small regulatory RNAs that are deregulated in a wide variety of human cancers, including different types of B-cell lymphoma. Nevertheless, the feasibility of circulating microRNA for early diagnosis of B-cell lymphoma has not been established. To address the possibility of detecting specific circulating microRNAs years before a B-cell lymphoma is diagnosed, we studied the plasma expression of microRNA first in pre-treatment samples from patients with diffuse large B-cell lymphoma and subsequently in repository samples from blood donors who later developed B-cell lymphomas. In addition, we studied the microRNA expression in the diagnostic lymphoma biopsy. The most strongly induced (miR-326) and suppressed (miR-375) plasma microRNA at diagnosis, when compared with healthy blood donors, were also substantially up- or down-regulated in plasma repository samples taken from several months to up to two years before the blood donors were diagnosed with B-cell lymphoma. Importantly, at these time points the donors had no signs of disease and felt healthy enough to donate blood. In conclusion, this first study of plasma microRNA profiles from apparently healthy individuals, taken several years before B-cell lymphoma diagnosis, suggests that plasma microRNA profiles may be predictive of lymphoma development. [ABSTRACT FROM AUTHOR]

The Harlequin ladybird Harmonia axyridis Pallas, native to eastern Asia, is an invasive, non-native species that has recently achieved an almost worldwide distribution. A conspicuous feature of this species is colour polymorphism of the elytra. In its native area, the populations consist of a recessive non-melanic morph, several dominant melanic morphs and small numbers of other (rare) morphs. The morph proportions in native populations have been intensively studied and vary with geographic area, climate and time. In contrast, colour polymorphism in invaded regions has been little studied. We examine and try to account for the morph frequencies observed across the different invaded regions. In America, monomorphic populations consist of the non-melanic morphs while European populations contain also melanic morphs. In particular geographic areas of Europe, the average percentage of the non-melanic morphs varied between 78 and 99%. It was highest in the lowlands of northern Italy and central and northern Europe and decreased in the Alps and western (Spain, UK) and eastern (southeast Russia) margins of the recently invaded area. In central Europe the frequency of the non-melanic morphs decreased over the course of the year but increased over the years from 2010 to 2018. The local differences might thus arise through gradual change of the morph composition of the founder invasive, non-native population. However, the variation in non-melanic morph frequency was not correlated with climatic characteristics that might affect coccinellid polymorphism. The observed rate of change in morph proportions in our data was too small to explain the diversification of what was supposedly a uniform invasive, non-native population at the point of introduction. [ABSTRACT FROM AUTHOR]

Foot–ground contact models play an important role in the accuracy of predictive human gait simulations, and there is a need for a computationally-efficient dynamic contact model for predictive and evaluative studies. In this research, we generated symbolic dynamic equations for a 2D torque-driven 11-DOF human model with a 3D ellipsoidal volumetric foot–ground contact model. The main goal was to increase the prediction accuracy and decrease the computation time for human gait analyses compared to the previous studies that used numerical formulations and point foot–ground contact models. A data-tracking optimization was developed to identify the contact parameters of the human gait model using two optimization approaches: trajectory optimization and optimal control. The first approach is developed with a global search algorithm based on inverse dynamics. In this algorithm, a local optimizer is repeatedly run from multiple potential start points to select the best start point while satisfying the constraints and reaching the lowest cost function value. The second approach is developed using direct collocation based on implicit dynamics. In this method, the optimization problem is solved using a variable-order adaptive orthogonal collocation method along with sparse nonlinear programming. Optimal control was superior to trajectory optimization for identifying a large number of parameters; the simulated torques and ground reaction forces from the optimal control correlated better with the experimental data. For the optimal control, the root-mean-square errors of the resultant torques, tangential and normal ground reaction forces were 0.48 (N.m), 14.07 (N), and 26.44 (N), respectively. However, for the trajectory optimization, these errors were 15.19 (N.m), 36.51 (N), and 234.57 (N). Thus, the optimized contact model from the optimal control, which was developed symbolically and based on volumetric contact equations, is a suitable foot–ground contact model for predictive human gait simulations. Additionally, we demonstrated that optimal control could be used to predict the motion and torque for the metatarsal joints, which are not easily measurable in practice. [ABSTRACT FROM AUTHOR]

Essential tremor manifests predominantly as a tremor of the upper limbs. One therapy option is high-frequency deep brain stimulation, which continuously delivers electrical stimulation to the ventral intermediate nucleus of the thalamus at about 130 Hz. Constant stimulation can lead to side effects, it is therefore desirable to find ways to stimulate less while maintaining clinical efficacy. One strategy, phase-locked deep brain stimulation, consists of stimulating according to the phase of the tremor. To advance methods to optimise deep brain stimulation while providing insights into tremor circuits, we ask the question: can the effects of phase-locked stimulation be accounted for by a canonical Wilson–Cowan model? We first analyse patient data, and identify in half of the datasets significant dependence of the effects of stimulation on the phase at which stimulation is provided. The full nonlinear Wilson–Cowan model is fitted to datasets identified as statistically significant, and we show that in each case the model can fit to the dynamics of patient tremor as well as to the phase response curve. The vast majority of top fits are stable foci. The model provides satisfactory prediction of how patient tremor will react to phase-locked stimulation by predicting patient amplitude response curves although they were not explicitly fitted. We also approximate response curves of the significant datasets by providing analytical results for the linearisation of a stable focus model, a simplification of the Wilson–Cowan model in the stable focus regime. We report that the nonlinear Wilson–Cowan model is able to describe response to stimulation more precisely than the linearisation. [ABSTRACT FROM AUTHOR]

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases. PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy is associated with both somatic and psychological side effects. Music might ease these problems. Several randomized controlled trials have investigated the effect of music, but the results are inconclusive. We aimed to examine whether live or pre-recorded music listening decreases anxiety during chemotherapy in newly diagnosed lymphoma patients.Methods: A total of 143 patients with non-Hodgkin and Hodgkin lymphomas were randomly assigned into three groups receiving either 30 min of patient-preferred live music (n = 47), 30 min of patient-preferred pre-recorded music (n = 47), or standard care (n = 49) during up to five outpatient chemotherapy sessions. The primary endpoint was anxiety measured by the Spielberger's State Anxiety Inventory. Secondary endpoints included blood pressure, pulse rate, nausea and vomiting, serum catecholamine levels pre- and post-intervention to measure arousal levels, and health-related quality of life. The Musical Ability Test was used to link musical ability to the primary endpoint.Results: When adjusting for age, sex, diagnosis, number of sessions, and baseline anxiety, the linear mixed model showed a borderline statistically significant reduction in the primary outcome anxiety in the live music group compared to standard care (7% (95% CI, - 14% to 0%, p = 0.05), while the effect of pre-recorded music was non-significant (5% (95% CI, - 12% to + 3%, p = 0.18). No intervention effects were seen in secondary outcomes.Conclusion: Our findings suggest that patient-preferred live music reduces anxiety among patients with malignant lymphomas undergoing chemotherapy. Musical ability among this group of cancer patients seems not to be a determining factor for effect of music intervention. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is an effective treatment for common movement disorders and has been used to modulate neural activity through delivery of electrical stimulation to key brain structures. The long-term efficacy of stimulation in treating disorders, such as Parkinson's disease and essential tremor, has encouraged its application to a wide range of neurological and psychiatric conditions. Nevertheless, adoption of DBS remains limited, even in Parkinson's disease. Recent failed clinical trials of DBS in major depression, and modest treatment outcomes in dementia and epilepsy, are spurring further development. These improvements focus on interaction with disease circuits through complementary, spatially and temporally specific approaches. Spatial specificity is promoted by the use of segmented electrodes and field steering, and temporal specificity involves the delivery of patterned stimulation, mostly controlled through disease-related feedback. Underpinning these developments are new insights into brain structure–function relationships and aberrant circuit dynamics, including new methods with which to assess and refine the clinical effects of stimulation. Advances in deep brain stimulation technologies are poised to improve outcomes in the clinic. [ABSTRACT FROM AUTHOR]

Following intense research efforts, modulation of the immune system has finally proved to be a viable approach for treating malignant disease. Recently, chimeric antigen receptor redirected T cells have achieved promising outcomes in patients with B-cell malignancies and they are currently also being investigated in other haematological malignancies, solid tumours and viral infections. Compared with traditional biopharmaceuticals, the properties of genetically modified chimeric antigen receptor redirected T-cell therapies differ in many aspects, thereby posing challenges in terms of post-authorisation data collection and data analysis. We believe that the network of population-based Nordic healthcare databases has some characteristics that can help provide important data on these new types of advanced products. In particular, the possibility of very long follow-up periods with a limited loss to follow-up is an important strength. Given the limited source population and slow access to data, a Nordic chimeric antigen receptor redirected T-cell monitoring project should be seen as complementary to other surveillance initiatives. [ABSTRACT FROM AUTHOR]

Foot-ground contact models are an important part of forward dynamic biomechanic models, particularly those used to model gait, and have many challenges associated with them. Contact models can dramatically increase the complexity of the multibody system equations, especially if the contact surface is relatively large or conforming. Since foot-ground contact has a large potential contact area, creating a computationally efficient model is challenging. This is particularly problematic in predictive simulations, which may determine optimal performance by running a model simulation thousands of times. An ideal contact model must find a balance between accuracy for large, conforming surfaces, and computational efficiency.Volumetric contact modelling is explored as a computationally efficient model for foot-ground contact. Previous foot models have used volumetric contact before, but were limited to 2D motion and approximated the surfaces as spheres or 2D shapes. The model presented here improves on current work by using ellipsoid contact geometry and considering 3D motion and geometry. A gait experiment was used to parametrise and validate the model. The model ran over 100 times faster than real-time (in an inverse simulation at 128 fps) and matched experimental normal force and centre of pressure location with less than 7% root-mean-square error.In most gait studies, only the net reaction forces, centre of pressure, and body motions are recorded and used to identify parameters. In this study, contact pressure was also recorded and used as a part of the identification, which was found to increase parameter optimisation time from 10 to 164 s (due to the additional time needed to calculate the pressure distribution) but helped the results converge to a more realistic model. The model matched experimental pressures with 33-45% root-mean-square error, though some of this was due to measurement errors.The same parametrisation was done with friction included in the foot model. It was determined that the velocity-based friction model that was used was inappropriate for use in an inverse-dynamics simulation. Attempting to optimise the model to match experimental friction resulted in a poor match to the experimental friction forces, inaccurate values for the coefficient of friction, and a poorer match to the experimental normal force. [ABSTRACT FROM AUTHOR]

Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology. [ABSTRACT FROM AUTHOR]

A theoretical analysis was performed for the production of Mo via the Mo(γ,n)Mo reaction using natural (Mo) and enriched (Mo) molybdenum targets in a modified NIRTA Targetry system. High energy electrons from a linear accelerator were simulated on a tungsten converter to produce bremsstrahlung incident on molybdenum targets using the TALYS computer code. All open channels and decay schemes were used to assess the production rates and final amounts of radioactive and stable components at end-of-bombardment (3-day irradiation), and after 2 h of cooling. Computations were performed at an accelerator energy of 40 MeV, correlating to a maximized photon fluence at 14 MeV. Impurities of Zr and Nb were found when utilizing enriched Mo (excluding Mo isotopes). Targets utilizing Mo added substantial stable and radioactive impurities of Mo, Nb, Zr, Y, and Sr; however, all but the Mo impurities can be readily separated. This study confirms the potential of producing Mo via Mo(γ,n)Mo using Mo with manageable impurities. [ABSTRACT FROM AUTHOR]

Context: The proportion of fire area that experienced stand-replacing fire effects is an important attribute of individual fires and fire regimes in forests, and this metric has been used to group forest types into characteristic fire regimes. However, relying on proportion alone ignores important spatial characteristics of stand-replacing patches, which can have a strong influence on post-fire vegetation dynamics. Objectives: We propose a new more ecologically relevant approach for characterizing spatial patterns of stand-replacing patches to account for potential limitation of conifer seed dispersal. Methods: We applied a simple modified logistic function to describe the relationship between the proportion of total stand-replacing patch area and an interior buffer distance on stand-replacing patches. Results: This approach robustly distinguishes among different spatial configurations of stand-replacing area in both theoretical and actual fires, and does so uniquely from commonly used descriptors of spatial configuration. Conclusions: Our function can be calculated for multiple fires over a given area, allowing for meaningful ecological comparisons of stand-replacing effects among different fires and regions. [ABSTRACT FROM AUTHOR]

Invasive alien predators are a serious threat to biodiversity worldwide. However, there is no generic method for assessing which local species are most at risk following the invasion of a new predator. The harlequin ladybird, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is an alien in Europe and many other parts of the world where it affects other species of ladybirds through competition for food and intra-guild predation (IGP). Here, we describe a method developed to assess which European ladybird species are most at risk following the invasion of H. axyridis. The three components of the risk assessment are: the likelihood that the assessed native species encounters H. axyridis in the field, the hazard of competition for food, and the IGP hazard. Thirty native European ladybird species were assessed through data obtained from field observations, laboratory experiments and literature reviews. The species that are considered most at risk are found on deciduous trees, have immature stages which are highly vulnerable to IGP by H. axyridis, and are primarily aphidophagous. These species should be the focus of specific studies and possibly conservation actions. The risk assessment method proposed here could be applied to other alien predators which are considered a threat to native species through competition and predation. [ABSTRACT FROM AUTHOR]

The linear sum assignment problem is a fundamental combinatorial optimisation problem and can be broadly defined as: given an $$n \times m, m \ge n$$ benefit matrix $$B = (b_{ij})$$ , matching each row to a different column so that the sum of entries at the row-column intersections is maximised. This paper describes the application of a new fast heuristic algorithm, Asymmetric Greedy Search, to the asymmetric version ( $$n \ne m$$ ) of the linear sum assignment problem. Extensive computational experiments, using a range of model graphs demonstrate the effectiveness of the algorithm. The heuristic was also incorporated within an algorithm for the non-sequential protein structure matching problem where non-sequential alignment between two proteins, normally of different numbers of amino acids, needs to be maximised. [ABSTRACT FROM AUTHOR]

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The harlequin ladybird, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is native to Asia but has been intentionally introduced to many countries as a biological control agent of pest insects. In numerous countries, however, it has been introduced unintentionally. The dramatic spread of H. axyridis within many countries has been met with considerable trepidation. It is a generalist top predator, able to thrive in many habitats and across wide climatic conditions. It poses a threat to biodiversity, particularly aphidophagous insects, through competition and predation, and in many countries adverse effects have been reported on other species, particularly coccinellids. However, the patterns are not consistent around the world and seem to be affected by many factors including landscape and climate. Research on H. axyridis has provided detailed insights into invasion biology from broad patterns and processes to approaches in surveillance and monitoring. An impressive number of studies on this alien species have provided mechanistic evidence alongside models explaining large-scale patterns and processes. The involvement of citizens in monitoring this species in a number of countries around the world is inspiring and has provided data on scales that would be otherwise unachievable. Harmonia axyridis has successfully been used as a model invasive alien species and has been the inspiration for global collaborations at various scales. There is considerable scope to expand the research and associated collaborations, particularly to increase the breadth of parallel studies conducted in the native and invaded regions. Indeed a qualitative comparison of biological traits across the native and invaded range suggests that there are differences which ultimately could influence the population dynamics of this invader. Here we provide an overview of the invasion history and ecology of H. axyridis globally with consideration of future research perspectives. We reflect broadly on the contributions of such research to our understanding of invasion biology while also informing policy and people. [ABSTRACT FROM AUTHOR]

We used a participatory approach and a rural livelihoods framework to explore the knowledge and capacity of southeast Queensland graziers to adapt to climate change. After being presented with information on climate change projections, participants identified biophysical and socio-economic opportunities and challenges to adaptation. Graziers identified key opportunities as components of resilience (incremental change), and in many cases were options that they had some knowledge of either from their own region or elsewhere in the grazing industry. The major constraint to adaptation was the lack of financial capital: with low profitability of the industry and high land costs restricting their capacity to diversify and exploit economies of scale. These constraints were exacerbated by the pressure many graziers experienced from the demand for land as a result of urban expansion. While the focus of the workshop was on the impact of climate change and capacity to adapt, many of the issues raised by graziers were pressures not solely related to climate change. Adaptation needs to be considered in light of the appropriate level (resilience-transition-transformation) and spatial scale (field to region) required to tackle the issues identified. Policy needs to support good natural resource management, rural amenity, and food and fibre production close to urban population and markets in the face of urban encroachment. [ABSTRACT FROM AUTHOR]

The article presents the authors' argument on the need for a complementary approach for an open community resource about the quality of new chemical probes or to reduce the use of low-quality chemical probes. They provide definition of a chemical probe and highlight soma examples of high quality chemical probes and probes of lesser value. They also describe plans of creating a web-based resource comprising of the most appropriate chemical probe for a given protein target.

Harmonia axyridis (Pallas) is an invasive ladybird spreading in several continents. It is native to East Asia, but its range in Asia has until now been poorly understood. The most complete map of the range of Harmonia axyridis in Asia has been compiled (432 localities). Harmonia axyridis occurs in the south-east of West Siberia, the south of East Siberia, the south of Russian Far East, the east of Kazakhstan, the north of Kyrgyzstan, Mongolia, China, North Korea, South Korea, Japan, and the north of Vietnam. Southeastern Kazakhstan and the north of Kyrgyzstan are not a part of the native range: the large Balkhash Desert is situated between this mountainous region and the nearest part of the native range (Altai mountains). The analysis of dates and places of findings indicates that Harmonia axyridis appeared in southeastern Kazakhstan and Kyrgyzstan after the construction of the Turkestan-Siberian Railway. It is hypothesized that the beetles crossed the desert along this railway. [ABSTRACT FROM AUTHOR]

Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m. The MTD of CEP-11981 was determined to be 97.4 mg/m, with DLTs observed at the 126.6 mg/m dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m and 1 patient at 126.6 mg/m), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased. [ABSTRACT FROM AUTHOR]

The Ultra-Violet Optical Telescope on the Swift spacecraft has observed hundreds of supernovae, covering all major types and most subtypes. Here we introduce the Swift Optical/Ultraviolet Supernova Archive (SOUSA), which will contain all of the supernova images and photometry. We describe the observation and reduction procedures and how they impact the final data. We show photometry from well-observed examples of most supernova classes, whose absolute magnitudes and colors may be used to infer supernova types in the absence of a spectrum. A full understanding of the variety within classes and a robust photometric separation of the groups requires a larger sample, which will be provided by the final archive. The data from the existing Swift supernovae are also useful for planning future observations with Swift as well as future UV observatories. [ABSTRACT FROM AUTHOR]