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Background Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.Methods We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).Findings Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35.2 months (IQR 31.5-41.3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.Interpretation Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Moving to a new school, while frequently exciting, is also filled withstress and anxiety for students and their parents. Nowhere is this moredeeply felt than during the transition from elementary to middle school.Increasingly schools are modifying their transition practices to assurethat students are better informed, and feel more secure in their new setting.This paper uses the construct of Invitational Education to identifyways in which school personnel can modify both formal and informaltransition activities to assure that students see their new school as welcomingand inviting.

[18F]FCH uptake in TSC2-deficient cells in vivo after 72-hr exposure to vehicle control (two representative mice).

Summary of FCH and FACE Imaging

Two bacterial strains able to use syringol as a sole carbon source were isolated from compost. The isolates, named S1 and S4, were sequenced using the Illumina platform. The final assemblies contained 4.2 Mbp, 63% GC, and 3,912 genes for S1 and 6.2 Mbp, 64% GC, and 5,503 genes for S4.

We provide the first documented case of whirling disease (WD) impacts to wild, self-sustaining rainbow trout (RNTR, Oncorynchus mykiss) populations in Canada. Myxobolus cerebralis (Mc), the causative agent of WD, was first confirmed in Alberta in 2016. However, evidence of disease in local fish populations was unknown. Using a weight-of-evidence approach, we examined multiple parasite life cycle stages in the Crowsnest River, Alberta. Percentage of infected Tubifex tubifex worms actively shedding triactinomyxons (TAMs) exceeded known thresholds of Mc establishment and TAM densities instream exceeded thresholds known to cause ≥90% declines in RNTR populations. Mc was detected at 5 of 6 study sites in water, fish, and worms. Disease severity was highest in the lower watershed where 100% of sentinel fish tested positive for Mc 7 to 14 days post-exposure; up to 85% of wild fingerling RNTR showed clinical signs of disease and yearling trout were largely absent from the river suggesting reduced survival. Our findings indicate conditions necessary for outbreak of WD exist in Alberta, highlighting the need to consider this disease as an emerging threat to wild salmonid populations.

The computational thinking (CT) method, Computing with concepts using tangible, computational tools, developed for humanistic subjects in higher education, is conceptualised as a 21st century competency in this theoretical article. The method aligns with the categories: Ways of thinking, Ways of working and Tools for working since it helps students build competencies in relation to generating ideas in novel and unconventional ways, in solving problems creatively and rigorously, and in representing and communicating ideas and solutions effectively and computationally. The method helps students engage in constructive dialogue, collaboratively explore abstract concepts and reflect on preferred ways of learning and personal biases, i.e. learn to learn. How CT activities map onto 21st century competencies is influenced by the learning theoretical framing, choice of technology and approach and the function of CT in the activity. The conclusion is that the CT method developed has potential not only as a relevant way for teachers and students in the humanities to work with CT and computational tools but also with respects to supporting students in building 21st century competencies.

Literature on the natural course of neuroinvasive West Nile virus (WNV) infection in solid organ transplant (SOT) recipients is sparse. In the setting of a 2021 WNV outbreak in Arizona, we reviewed our institution's experience with neuroinvasive WNV infection in patients with SOT.We retrospectively identified SOT recipients treated for neuroinvasive WNV at Mayo Clinic in Arizona from 2007 through 2021. Clinical manifestations, disease course, and outcomes were analyzed.Among 24 SOT recipients with WNV infection identified during the study period, 13 infections occurred in 2021. Most patients had gastrointestinal tract symptoms and fever at disease presentation. Five patients had cognitive impairment, and 14 initially or eventually had acute flaccid paralysis. Clinically significant deterioration occurred at a median of 4 (range, 1-11) days after hospital admission. Seventeen patients (71%) were transferred to the intensive care unit, with 15 requiring mechanical ventilation. Initial cerebrospinal fluid analysis mainly demonstrated a neutrophil-predominant pleocytosis. Almost all patients (n = 23) were treated with intravenous immunoglobulin alone or in combination with interferon alfa-2b. Sixteen patients had clinical improvement, 4 of whom recovered completely. Six patients died during hospitalization due to complications of neuroinvasive WNV infection. Two patients were discharged to hospice without clinical recovery. The overall 30-day mortality rate was 36%.Despite advances in supportive care, neuroinvasive WNV infection is associated with substantial morbidity and mortality in SOT recipients. Flaccid paralysis is an indicator of poor prognosis. This article is protected by copyright. All rights reserved.

BackgroundHydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.Methods and resultsWhole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.ConclusionPathogenic heterozygousANGPT2missense variants were recently shown to cause autosomal dominant primary lymphoedema.ANGPT2is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessiveANGPT2-related disorder in humans.

Vocabulary acquisition is an integral part of learning a language which involves a challenging process. Hence, the implementation of efficient vocabulary learning strategies should be done among different English classes to make it easier for students to enhance their vocabulary skills. While the pandemic made it more challenging for learners to study and master English vocabulary, the rise of online instructional materials is highly appreciated for it is more convenient for the students to learn. This quasi-experimental study was an attempt to determine the effectiveness of an Online Remediation Program in enhancing the vocabulary skills of Junior High School students. A total of 20 Grade 7 students from University of Saint Louis participated in the online remediation program and answered the vocabulary pre-test and post-test. The researchers utilized pre-test and post-test that were consisted of a 30-item multiple choice to measure the vocabulary skills of the participants. This study followed three phases of data gathering: First, a pre-test was administered to the participants before the utilization of the proposed vocabulary development remediation program. Second, the proposed vocabulary development remediation program was implemented to the target participants. Third, a post-test was administered to the participants after the utilization of the vocabulary development remediation program. Frequency and percentage was used to interpret the pre-test and post-test scores of the participants while independent sample T-test was used to test the significant difference between their pre-test and post-test scores. Results revealed that the post-test scores of the students were higher than their pre-test scores. In addition, the findings showed that there is a significant difference on the pre-test and post-test scores of the participants. Finally, the overall evaluation of the participants to the Online Remediation Program is Excellent. Thus, the study concludes that the utilization of Project STRIVE is effective in enhancing the vocabulary skills of Grade 7 students.

PURPOSE OF REVIEW This article reviews the neurologic complications associated with human immunodeficiency virus (HIV) infection. RECENT FINDINGS Neurologic complications of HIV may be caused by direct virally mediated pathology, immune-mediated phenomena in response to viral infection, or opportunistic infections secondary to depletion of lymphocytes. These neurologic disorders may be influenced by the degree of immunosuppression (ie, CD4+ T-cell lymphocyte count) and stage of infection (early versus late), as well as use of antiretroviral therapy, and may manifest as a variety of central and peripheral neurologic syndromes, including the more commonly encountered HIV-associated cognitive disorders and length-dependent sensorimotor polyneuropathy, respectively. Immune dysregulation underlies the majority of these neurologic phenomena, as well as other HIV-associated conditions including immune reconstitution inflammatory syndrome (IRIS), CD8 lymphocytosis, and potentially the development of compartmentalized infection within the CSF, also referred to as CSF escape. SUMMARY This article reviews a spectrum of clinical syndromes and related neuropathologic states associated with HIV infection.