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Background Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinically, the LQ model is mainly used to estimate equivalent radiotherapy schedules (e.g. calculate the equivalent dose in 2 Gy fractions, EQD 2 ), but increasingly also to predict tumour control probability (TCP) and normal tissue complication probability (NTCP) using logistic models. The selection of accurate LQ parameters α, β and α/β is pivotal for a reliable estimate of radiation response. The aim of this review is to provide an overview of published values for the LQ parameters of human tumours as a guideline for radiation oncologists and radiation researchers to select appropriate radiobiological parameter values for LQ modelling in clinical radiotherapy. Methods and materials We performed a systematic literature search and found sixty-four clinical studies reporting α, β and α/β for tumours. Tumour site, histology, stage, number of patients, type of LQ model, radiation type, TCP model, clinical endpoint and radiobiological parameter estimates were extracted. Next, we stratified by tumour site and by tumour histology. Study heterogeneity was expressed by the I 2 statistic, i.e. the percentage of variance in reported values not explained by chance. Results A large heterogeneity in LQ parameters was found within and between studies (I 2  > 75%). For the same tumour site, differences in histology partially explain differences in the LQ parameters: epithelial tumours have higher α/β values than adenocarcinomas. For tumour sites with different histologies, such as in oesophageal cancer, the α/β estimates correlate well with histology. However, many other factors contribute to the study heterogeneity of LQ parameters, e.g. tumour stage, type of LQ model, TCP model and clinical endpoint (i.e. survival, tumour control and biochemical control). Conclusions The value of LQ parameters for tumours as published in clinical radiotherapy studies depends on many clinical and methodological factors. Therefore, for clinical use of the LQ model, LQ parameters for tumour should be selected carefully, based on tumour site, histology and the applied LQ model. To account for uncertainties in LQ parameter estimates, exploring a range of values is recommended.

Linked administrative population data were used to estimate the burden of childhood respiratory syncytial virus (RSV) hospitalization in an Australian cohort aged <5 years. RSV-coded hospitalizations data were extracted for all children aged <5 years born in New South Wales (NSW), Australia between 2001 and 2010. Incidence was calculated as the total number of new episodes of RSV hospitalization divided by the child-years at risk. Mean cost per episode of RSV hospitalization was estimated using public hospital cost weights. The cohort comprised of 870 314 children. The population-based incidence/1000 child-years of RSV hospitalization for children aged <5 years was 4·9 with a rate of 25·6 in children aged <3 months. The incidence of RSV hospitalization (per 1000 child-years) was 11·0 for Indigenous children, 81·5 for children with bronchopulmonary dysplasia (BPD), 10·2 for preterm children with gestational age (GA) 32–36 weeks, 27·0 for children with GA 28–31 weeks, 39·0 for children with GA <28 weeks and 6·7 for term children with low birthweight. RSV hospitalization was associated with an average annual cost of more than AUD 9 million in NSW. RSV was associated with a substantial burden of childhood hospitalization specifically in children aged <3 months and in Indigenous children and children born preterm or with BPD.

SummaryWe conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups.IntroductionVitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women.MethodsWe conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 μg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 μg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT.ResultsUndercarboxylated osteocalcin decreased in the MK-7-group (− 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (− 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score.ConclusionTreatment with MK-7 375 μg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture.Trial registrationThe study was registered at Clinicaltrial.gov:NCT01922804.

The currently available arsenal of anticancer modalities includes many DNA damaging agents that can kill malignant cells. However, efficient DNA repair mechanisms protect both healthy and cancer cells against the effects of treatment and contribute to the development of drug resistance. Therefore, anti-cancer treatments based on inflicting DNA damage can benefit from inhibition of DNA repair. Hyperthermia – treatment at elevated temperature – considerably affects DNA repair, among other cellular processes, and can thus sensitize (cancer) cells to DNA damaging agents. This effect has been known and clinically applied for many decades, but how heat inhibits DNA repair and which pathways are targeted has not been fully elucidated. In this review we attempt to summarize the known effects of hyperthermia on DNA repair pathways relevant in clinical treatment of cancer. Furthermore, we outline the relationships between the effects of heat on DNA repair and sensitization of cells to various DNA damaging agents.

When sustained for megayears (refs.  1 , 2 ), high-power jets from supermassive black holes (SMBHs) become the largest galaxy-made structures in the Universe 3 . By pumping electrons, atomic nuclei and magnetic fields into the intergalactic medium (IGM), these energetic flows affect the distribution of matter and magnetism in the cosmic web 4 – 6 and could have a sweeping cosmological influence if they reached far at early epochs. For the past 50 years, the known size range of black hole jet pairs ended at 4.6–5.0 Mpc (refs.  7 – 9 ), or 20–30% of a cosmic void radius in the Local Universe 10 . An observational lack of longer jets, as well as theoretical results 11 , thus suggested a growth limit at about 5 Mpc (ref.  12 ). Here we report observations of a radio structure spanning about 7 Mpc, or roughly 66% of a coeval cosmic void radius, apparently generated by a black hole between 4.4 − 0.7 + 0.2 and 6.3 Gyr after the Big Bang. The structure consists of a northern lobe, a northern jet, a core, a southern jet with an inner hotspot and a southern outer hotspot with a backflow. This system demonstrates that jets can avoid destruction by magnetohydrodynamical instabilities over cosmological distances, even at epochs when the Universe was 7 to 1 5 − 2 + 6 times denser than it is today. How jets can retain such long-lived coherence is unknown at present. Radio images reveal distant black hole jets of cosmological length, suggesting that the environmental impact of supermassive black holes extends further in space and time than previously thought.

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear (‘inverted U-shaped’) effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans. We hypothesised that diverse effects of dopamine neuromodulation could be characterised using systems-level neuroimaging approaches. Using ‘resting-state’ functional magnetic resonance imaging (FMRI), combined with dopaminergic challenges, we examined the dopamine-dependent functional connectivity of brain ‘resting-state networks’ (RSNs). We compared RSN connectivity in 3 groups of healthy volunteers given dopamine antagonist (haloperidol; N=18) or agonistic (levodopa; N=16) drugs, or a placebo (N=15). As RSNs have been shown to be relevant for numerous psychological functions and dysfunctions, we investigated both linear and nonlinear effects on RSN connectivity of manipulating dopamine neurotransmission pharmacologically. A basal ganglia RSN displayed both linear and nonlinear effects of dopamine manipulation on functional connectivity, respectively, with lateral frontoparietal and medial frontal neocortical areas. Conversely, a cognitive ‘default mode’ network showed only linear dopaminergic effects on connectivity with lateral frontal and parietal cortices. Our findings highlight diverse functional effects of dopamine neuromodulations on systems-level neural interactions. The observation that dopamine modulates distinct large-scale network connectivity patterns differentially, in both linear and nonlinear fashions, provides support for the objective utility of RSN metrics in classifying the effects and efficacy of psychopharmacological medications. •Dopamine agonism and antagonism differentially affect large-scale brain networks.•The same drugs can also exert comparable modulations over distinct neurocircuitry.•Network-level drug effects are relevant for impulsive personality characteristics.•Resting-state FMRI may stratify psychopharmacological responses across individuals.

To review and summarise the literature reporting on cannabis use within western communities with specific reference to patterns of use, the pharmacology of its major psychoactive compounds, including placental and fetal transfer, and the impact of maternal cannabis use on pregnancy, the newborn infant and the developing child. Review of published articles, governmental guidelines and data and book chapters. Although cannabis is one of the most widely used illegal drugs, there is limited data about the prevalence of cannabis use in pregnant women, and it is likely that reported rates of exposure are significantly underestimated. With much of the available literature focusing on the impact of other illicit drugs such as opioids and stimulants, the effects of cannabis use in pregnancy on the developing fetus remain uncertain. Current evidence indicates that cannabis use both during pregnancy and lactation, may adversely affect neurodevelopment, especially during periods of critical brain growth both in the developing fetal brain and during adolescent maturation, with impacts on neuropsychiatric, behavioural and executive functioning. These reported effects may influence future adult productivity and lifetime outcomes. Despite the widespread use of cannabis by young women, there is limited information available about the impact perinatal cannabis use on the developing fetus and child, particularly the effects of cannabis use while breast feeding. Women who are using cannabis while pregnant and breast feeding should be advised of what is known about the potential adverse effects on fetal growth and development and encouraged to either stop using or decrease their use. Long-term follow-up of exposed children is crucial as neurocognitive and behavioural problems may benefit from early intervention aimed to reduce future problems such as delinquency, depression and substance use.

The urokinase plasminogen activator receptor (uPAR) plays a multifaceted role in almost any process where migration of cells and tissue-remodeling is involved such as inflammation, but also in diseases as arthritis and cancer. Normally, uPAR is absent in healthy tissues. By its carefully orchestrated interaction with the protease urokinase plasminogen activator and its inhibitor (plasminogen activator inhibitor-1), uPAR localizes a cascade of proteolytic activities, enabling (patho)physiologic cell migration. Moreover, via the interaction with a broad range of cell membrane proteins, like vitronectin and various integrins, uPAR plays a significant, but not yet completely understood, role in differentiation and proliferation of cells, affecting also disease progression. The implications of these processes, either for diagnostics or therapeutics, have received much attention in oncology, but only limited beyond. Nonetheless, the role of uPAR in different diseases provides ample opportunity to exploit new applications for targeting. Especially in the fields of oncology, cardiology, rheumatology, neurology, and infectious diseases, uPAR-targeted molecular imaging could offer insights for new directions in diagnosis, surveillance, or treatment options.