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The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2–6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1–5, cyclophosphamide 150 mg/m2 per day orally on days 1–5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56–67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41–61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63–NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32–0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. Cancer Research UK and Janssen.

The Arctic is one of the most rapidly warming regions of the Earth, with predicted temperature increases of 5–7 ∘C and the accompanying extensive retreat of Arctic glacial systems by 2100. Retreating glaciers will reveal new land surfaces for microbial colonisation, ultimately succeeding to tundra over decades to centuries. An unexplored dimension to these changes is the impact upon the emission and consumption of halogenated organic compounds (halocarbons). Halocarbons are involved in several important atmospheric processes, including ozone destruction, and despite considerable research, uncertainties remain in the natural cycles of some of these compounds. Using flux chambers, we measured halocarbon fluxes across the glacier forefield (the area between the present-day position of a glacier's ice-front and that at the last glacial maximum) of a high-Arctic glacier in Svalbard, spanning recently exposed sediments (<10 years) to approximately 1950-year-old tundra. Forefield land surfaces were found to consume methyl chloride (CH3Cl) and methyl bromide (CH3Br), with both consumption and emission of methyl iodide (CH3I) observed. Bromoform (CHBr3) and dibromomethane (CH2Br2) have rarely been measured from terrestrial sources but were here found to be emitted across the forefield. Novel measurements conducted on terrestrial cyanobacterial mats covering relatively young surfaces showed similar measured fluxes to the oldest, vegetated tundra sites for CH3Cl, CH3Br, and CH3I (which were consumed) and for CHCl3 and CHBr3 (which were emitted). Consumption rates of CH3Cl and CH3Br and emission rates of CHCl3 from tundra and cyanobacterial mat sites were within the ranges reported from older and more established Arctic tundra elsewhere. Rough calculations showed total emissions and consumptions of these gases across the Arctic were small relative to other sources and sinks due to the small surface area represented by glacier forefields. We have demonstrated that glacier forefields can consume and emit halocarbons despite their young age and low soil development, particularly when cyanobacterial mats are present.

Abstract Background. This study investigates the impact of childhood maltreatment (CM) on hypothalamic- pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. Methods. In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. Results. Youth with a CM history had higher overall diurnal cortisol levels ( p = 0.001), blunted cortisol response to acute psychosocial stress ( p = 0.002) and greater perceived anxiety ( p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output ( pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C ( pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM ( p < 0.001), regardless of its severity/frequency. Conclusions. Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions.

The Arctic is one of the most rapidly warming regions of the Earth, with predicted temperature increases of 5-7 .sup.\" C and the accompanying extensive retreat of Arctic glacial systems by 2100. Retreating glaciers will reveal new land surfaces for microbial colonisation, ultimately succeeding to tundra over decades to centuries. An unexplored dimension to these changes is the impact upon the emission and consumption of halogenated organic compounds (halocarbons). Halocarbons are involved in several important atmospheric processes, including ozone destruction, and despite considerable research, uncertainties remain in the natural cycles of some of these compounds. Using flux chambers, we measured halocarbon fluxes across the glacier forefield (the area between the present-day position of a glacier's ice-front and that at the last glacial maximum) of a high-Arctic glacier in Svalbard, spanning recently exposed sediments (<10 years) to approximately 1950-year-old tundra. Forefield land surfaces were found to consume methyl chloride (CH.sub.3 Cl) and methyl bromide (CH.sub.3 Br), with both consumption and emission of methyl iodide (CH.sub.3 I) observed. Bromoform (CHBr.sub.3) and dibromomethane (CH.sub.2 Br.sub.2) have rarely been measured from terrestrial sources but were here found to be emitted across the forefield. Novel measurements conducted on terrestrial cyanobacterial mats covering relatively young surfaces showed similar measured fluxes to the oldest, vegetated tundra sites for CH.sub.3 Cl, CH.sub.3 Br, and CH.sub.3 I (which were consumed) and for CHCl.sub.3 and CHBr.sub.3 (which were emitted). Consumption rates of CH.sub.3 Cl and CH.sub.3 Br and emission rates of CHCl.sub.3 from tundra and cyanobacterial mat sites were within the ranges reported from older and more established Arctic tundra elsewhere. Rough calculations showed total emissions and consumptions of these gases across the Arctic were small relative to other sources and sinks due to the small surface area represented by glacier forefields. We have demonstrated that glacier forefields can consume and emit halocarbons despite their young age and low soil development, particularly when cyanobacterial mats are present.

The Arctic is one of the most rapidly warming regions of the Earth, with predicted temperature increases of 5–7 ∘C and the accompanying extensive retreat of Arctic glacial systems by 2100. Retreating glaciers will reveal new land surfaces for microbial colonisation, ultimately succeeding to tundra over decades to centuries. An unexplored dimension to these changes is the impact upon the emission and consumption of halogenated organic compounds (halocarbons). Halocarbons are involved in several important atmospheric processes, including ozone destruction, and despite considerable research, uncertainties remain in the natural cycles of some of these compounds. Using flux chambers, we measured halocarbon fluxes across the glacier forefield (the area between the present-day position of a glacier's ice-front and that at the last glacial maximum) of a high-Arctic glacier in Svalbard, spanning recently exposed sediments (<10 years) to approximately 1950-year-old tundra. Forefield land surfaces were found to consume methyl chloride (CH3Cl) and methyl bromide (CH3Br), with both consumption and emission of methyl iodide (CH3I) observed. Bromoform (CHBr3) and dibromomethane (CH2Br2) have rarely been measured from terrestrial sources but were here found to be emitted across the forefield. Novel measurements conducted on terrestrial cyanobacterial mats covering relatively young surfaces showed similar measured fluxes to the oldest, vegetated tundra sites for CH3Cl, CH3Br, and CH3I (which were consumed) and for CHCl3 and CHBr3 (which were emitted). Consumption rates of CH3Cl and CH3Br and emission rates of CHCl3 from tundra and cyanobacterial mat sites were within the ranges reported from older and more established Arctic tundra elsewhere. Rough calculations showed total emissions and consumptions of these gases across the Arctic were small relative to other sources and sinks due to the small surface area represented by glacier forefields. We have demonstrated that glacier forefields can consume and emit halocarbons despite their young age and low soil development, particularly when cyanobacterial mats are present.

Background Previous prospective studies have found the incidence of intestinal diverticular disease decreased with increasing intakes of dietary fibre, but associations by the fibre source are less well characterised. We assessed these associations in a large UK prospective study of middle-aged women. Methods and findings During 6 (SD 1) years follow-up of 690 075 women without known diverticular disease who had not changed their diet in the last 5 years, 17 325 were admitted to hospital or died with diverticular disease. Dietary fibre intake was assessed using a validated 40-item food questionnaire and remeasured 1 year later in 4265 randomly-selected women. Mean total dietary fibre intake at baseline was 13.8 (SD 5.0) g/day, of which 42% came from cereals, 22% from fruits, 19% from vegetables (not potatoes) and 15% from potatoes. The relative risk (95% CI) for diverticular disease per 5 g/day fibre intake was 0.86 (0.84 to 0.88). There was significant heterogeneity by the four main sources of fibre (p<0.0001), with relative risks, adjusted for each of the other sources of dietary fibre of 0.84 (0.81 to 0.88) per 5 g/day for cereal, 0.81 (0.77 to 0.86) per 5 g/day for fruit, 1.03 (0.93 to 1.14) per 5 g/day for vegetable and 1.04 (1.02 to 1.07) per 1 g/day for potato fibre. Conclusions A higher intake of dietary fibre is associated with a reduced risk of diverticular disease. The associations with diverticular disease appear to vary by fibre source, and the reasons for this variation are unclear.

Objective To compare the testicular Color Doppler ultrasound (US), hormone levels, and histological results from 67 infertile men with Klinefelter syndrome (KS), vs. 66 non-KS non-obstructive azoospermic men. Methods Scrotal US images were collected from 67 infertile KS and 66 non-obstructive, non-KS azoospermic men. The testis volume, echotexture, vascularity, and microliths were evaluated and graded. We defined the following echo pattern alteration groups: normal, striated, coarse, and measurable nodules. The vascularization was classified as low, normal, moderate, or strong. Testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B levels were determined. Large testicular nodules were removed. A testicular biopsy and sperm extraction was performed in 18 of the KS, and all of the 66 non-KS men. Results The mean testis volume was low in the KS, compared to the non-KS patients: i.e., 2 vs. 8 mL ( P  < 0.0001). The distributions in the echotexture groups differed markedly, with coarse or nodular patterns in the KS men, and normal/striated patterns in the control patients ( P  < 0.0001). The vascularization and microlithiasis grades were higher in the KS patients than the control men ( P  < 0.0001 and P  < 0.001, respectively). All of the nodules removed from the KS patients were benign Leydig cell tumors, and all of the biopsies showed marked Leydig cell hyperplasia, with spermatogenesis in only two patients. The non-KS biopsies were predominantly Sertoli cell-only syndrome. Conclusions Small testes, with a coarse or nodular echotexture, hypervascularization, and microlithiasis are associated with KS. The KS nodules were benign Leydig cell tumors/hyperplasias.

Childhood maltreatment (CM) is associated with increased non-suicidal self-injury (NSSI) and suicidal behavior (SB), independently of demographic and mental health conditions. Self-Trauma Theory and Linehan's Biopsychosocial Model might explain the emergence of Borderline Personality Disorder (BPD) symptoms as mediators of the association between CM and the risk of SB. However, little is known regarding such relationships when the exposure is recent for young persons. Here, we study 187 youths aged 7-17, with or without mental disorders. We explore CM experiences (considering the severity and frequency of different forms of neglect and abuse), recent stressful life events (SLEs), some BPD traits (emotion dysregulation, intense anger and impulsivity), and the risk of SB (including NSSI, suicide threat, suicide ideation, suicide plan and suicide attempt). We study the direct and mediating relationships between these variables via a structural equation analysis using the statistical software package EQS. Our findings suggest that youths exposed to more severe/frequent CM have more prominent BPD traits, and are more likely to have experienced recent SLEs. In turn, BPD traits increase the risk of SLEs. However, only emotion dysregulation and recent SLEs were found to be correlated with SB. Therefore, targeted interventions on emotion dysregulation are necessary to prevent NSSI or SB in children and adolescents exposed to CM, as is the minimization of further SLEs. Keywords: borderline personality disorder traits; childhood maltreatment; complex trauma; emotion dysregulation; non-suicidal self-injury (NSSI); stressful life event (SLE); suicidal behavior (SB); youth.

THE fossil record of early vertebrates starts with certainty with the dermal armour of agnathan fish from the Early–Middle Ordovician of Australia 1,2 . Recent controversial acceptance that conodonts 3 and the fragments called Anatolepis 4,5 may be vertebrate remains 6 , extends their fossil record back to the Late Cambrian. Now a new type of phosphatic skeleton from Australia shows a three-layered structure that indicates vertebrate affinity, but with several unique features not known in other vertebrates. The new evidence challenges the most widely accepted current theory for the development of the vertebrate skeleton 7–11 , which assumes the odontode (skin denticle) to be the primitive patterning component. The Australian material provides an alternative model for early vertebrate dermal armour with which to assess the vertebrate-like hard tissues in conodonts 12,13 and the dermal armour of Anatolepis 4–6,14 .