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\"Schizophrenia is a chronic disorder that impacts a broad range of a person's social and developmental functioning. Until the recent past, most of the research done on schizophrenia did not include children or adolescents who suffer from the disorder. During adolescence, important changes take place in brain development. These changes make adolescence a period of both vulnerability and opportunity. Emergence of psychosis and schizophrenia may be associated with abnormal brain development during adolescence. This book discusses the findings of studies that focus on abnormal brain development during the premorbid period of psychosis and schizophrenia. Cognitive neuroscience constructs of visuospatial memory and working memory are associated with adult- and adolescent-onset schizophrenia. This book reviews the existing literature on the topic and explores the nature of and association between visuospatial memory in adolescent onset schizophrenia.\"--Preface.

Adenovirus type 2 (Ad2) imports its DNA genome through the nuclear pore complex (NPC) of cells in interphase for viral production. Here we identify the NPC-filament protein CAN/Nup214 as a docking site for incoming Ad2 capsids. Binding to CAN is independent of cytosolic factors. Capsids disassemble at NPCs to free their DNA for import. This process requires binding of nuclear histone H1 to the stably docked capsids and involves H1-import factors, restricting this irreversible process to the proximity of the nucleus. Our results provide a molecular mechanism for disassembly of Ad2 and reveal an unexpected function of histone H1 in virus-mediated DNA import.

In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58–74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2–6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5–18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66–94), and the estimated 18 month overall survival rate was 97% (95% CI 79–100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3–11·7) increased to 11·4 g/dL (10·9–12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8–13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Pharmacyclics LLC, an AbbVie Company.

IntroductionPatients with hematological malignancies are at high risk of infections due to both the disease and the associated treatments. The use of immunoglobulin (Ig) to prevent infections is increasing in this population, but its cost effectiveness is unknown. This trial-based economic evaluation aimed to compare the cost effectiveness of prophylactic Ig with prophylactic antibiotics in patients with hematological malignancies.MethodsThe economic evaluation used individual patient data from the RATIONAL feasibility trial, which randomly assigned 63 adults with chronic lymphocytic leukemia, multiple myeloma, or lymphoma to prophylactic Ig or prophylactic antibiotics. The following two analyses were conducted to estimate the cost effectiveness of the two treatments over the 12-month trial period from the perspective of the Australian health system:(i) a cost-utility analysis (CUA) to assess the incremental cost per quality-adjusted life-year (QALY) gained using data collected with the EuroQol 5D-5L questionnaire; and(ii) a cost-effectiveness analysis (CEA) to assess the incremental cost per serious infection prevented (grade ≥3) and per infection prevented (any grade).ResultsThe total cost per patient was significantly higher in the Ig arm than in the antibiotic arm (difference AUD29,140 [USD19,000]). There were non-significant differences in health outcomes between the treatment arms: patients treated with Ig had fewer QALYs (difference −0.072) and serious infections (difference −0.26) than those given antibiotics, but more overall infections (difference 0.76). The incremental cost-effectiveness from the CUA indicated that Ig was more costly than antibiotics and associated with fewer QALYs. In the CEA, Ig costed an additional AUD111,262 (USD73,000) per serious infection prevented, but it was more costly than antibiotics and associated with more infections when all infections were included.ConclusionsThese results indicate that, on average, Ig prophylactic treatment may not be cost effective compared with prophylactic antibiotics for the group of patients with hematological malignancies recruited to the RATIONAL feasibility trial. Further research is needed to confirm these findings in a larger population and over the longer term.

Rewilding initiatives are increasing in number across Europe and the UK in response to a growing awareness of substantial nature depletion, despite a lack of policy, guidance and legislation. Ongoing transformations of UK environmental policies offer a ‘policy window’ in which rewilding could become established as a key strategy for nature recovery. Here, we present the results of discussion sessions held as part of a British Ecological Society Policy Training workshop. A total of 46 participants, academics, practitioners and young people interested in rewilding attended. Our discussion focused on three pre‐determined thematic discussion sessions: (1) barriers to rewilding and trade‐offs; (2) species reintroductions; (3) facilitating rewilding in policy. Using thematic analysis, four emerging cross‐cutting themes were identified from our workshop discussions: (a) environmental stewardship & public engagement, (b) cross‐policy approaches, (c) incentivising rewilding and (d) an evidence base for rewilding. Policy Implications. Given the UK's considerable biodiversity loss, restoring ecosystem processes and function on a large scale is increasingly urgent, and operationalising rewilding through supportive environmental policy structures should be a key priority for government. Read the free Plain Language Summary for this article on the Journal blog. Read the free Plain Language Summary for this article on the Journal blog.