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Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.

For students with disabilities (SWD), note taking during content area classes can be a puzzling process. Students often are not certain about what specific content to record, how many details to record, and how to write fast enough to keep up with the teacher. Smartpens are an underutilized type of technology that can help students to become better note takers by storing verbal information during lectures and syncing it up later when students amend their notes. This article provides an overview of different types of smartpens and information for teachers about how to use smartpens in the classroom.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome that complicates hematopoietic stem cell transplant (HSCT). Morbidity and mortality from TA-TMA remain high, making prevention critical. We describe our retrospective single-center experience of TA-TMA after pediatric allogeneic HSCT and present a novel pre-HSCT risk-stratification system and prophylaxis regimen. From January 2012 through October 2019, 257 patients underwent 292 allogeneic HSCTs. Prospective risk stratification was introduced in December 2016. High-risk (HR) patients were treated with combination prophylaxis with eicosapentaenoic acid and N-acetylcysteine. The 1-year cumulative incidence of TA-TMA was 6.3% (95% confidence interval [CI], 3.2-9.4). Age ≥10 years, myeloablative conditioning with total body irradiation, HLA mismatch, diagnosis of severe aplastic anemia or malignancy, prior calcineurin inhibitor exposure, and recipient cytomegalovirus seropositivity were found to be pre-HSCT risk factors for development of TA-TMA. Before routine prophylaxis, TA-TMA rates were significantly different between the HR and standard-risk groups, at 28.2% (95% CI, 0-12.7) vs 3.2% (0.1-6.3), respectively (P < .001). After introduction of prophylaxis, the 1-year cumulative incidence of TA-TMA in the HR group decreased to 4.5% (95% CI, 0-13.1; P = .062, compared with the incidence before prophylaxis). Multicenter pediatric studies are needed to validate these risk criteria and to confirm the efficacy of the prophylactic regimen.

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool. Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit. Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care. Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

IntroductionGenetic-guided selection of non-oncologic medications is not commonly practiced in general, and at University of California, San Francisco (UCSF) Health, specifically. Understanding the unique position of clinicians with respect to clinical pharmacogenetics (PG) at a specific institution or practice is fundamental for implementing a successful PG consult service.ObjectivesTo assess clinicians' current practices, needs, and interests with respect to clinical PG at UCSF Health, a large tertiary academic medical center.MethodsA list of 42 target medications with clinical PG recommendations was complied. Clinical specialties that routinely used the target medications were identified. A 12-question survey focused on practice of PG for target medications was developed. Pharmacists and physicians were surveyed anonymously in several clinical specialties. Survey results were analyzed using descriptive statistics.ResultsOf the 396 clinicians surveyed, 76 physicians and 59 pharmacists participated, resulting in 27% and 50% average response rates, respectively. The current use of PG in clinical practice for physicians and pharmacists was 29% and 32%, respectively, however this number varied across clinical specialties from 0% to 80%. Of clinicians whom reported they do not currently apply PG, 63% of physicians and 54% of pharmacists expressed interest in integrating PG. However, the level of interest varied from 20% to 100% across specialties. Of the respondents, 64% of physicians and 56% of pharmacists elected to provide contact information to investigators to further discuss their interest related to clinical PG.ConclusionsWhile PG is not uniformly practiced at UCSF Health, there is considerable interest in utilizing PG by the respondents. Our approach was successful at identifying clinicians and services interested in PG for specific drug-gene pairs. This work has set a foundation for next steps to advance PG integration at UCSF Health. Clinicians can adopt our approach as preliminary work to build a clinical PG program at their institutions.

BackgroundAllogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.MethodsWe performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.ResultsEight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.ConclusionsLentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).

Students with disabilities (SWD; e.g., learning disabilities) often struggle with slower processing speed and poor working memory skills, which reduce the quality of their notes. This study evaluated the effects of a note-taking intervention using the researcher-created smartpen strategy in conjunction with the assistive technology of the Livescribe™ Smartpen to assess the effects of students' overall notes and lecture comprehension. Both SWD and without disabilities in ninth-grade English Language Arts classes participated in this study. The note-taking intervention was designed to assist SWD to take notes using the smartpen assistive technology, aid students in identifying key vocabulary content, amend their notes for errors or missed information, and establish a summary of the lecture. Results from the data analysis found that SWD in the experimental group recorded more words in their notes, as well as an increase in word count on the immediate free recall assessment.

Vascular surgery registries report on procedures and outcomes to promote patient safety and drive quality improvement. International registries have contributed significantly to the VASCUNET collaborative abdominal aortic aneurysm (AAA) outcome projects. This scoping review aimed to outline the national registries in vascular surgery that currently participate in the VASCUNET collaborative AAA projects. A scoping review of all published VASCUNET AAA studies and validation reports between 1997 and 2024 was undertaken. A survey was conducted among representatives of the international vascular registries contributing to VASCUNET collaborative AAA projects. Currently, vascular registries from 10 countries (Australia, Denmark, Finland, Hungary, Iceland, New Zealand, Norway, Sweden, Switzerland, and the UK) contribute to the current VASCUNET collaborative AAA project, of which eight have national coverage. In the past, three countries (Germany, Malta, and Italy) have participated in previous VASCUNET AAA projects, and a further three countries (Serbia, Greece, and Portugal) have planned participation in future projects. External validity is high for all current registries, with most reporting rates of > 90%. The majority have internal validation processes to assess data accuracy. VASCUNET mediated validation has also been performed by the consortium for five countries to date (Hungary, Sweden, Denmark, Malta, and Switzerland), for which a high degree of external and internal validity was identified. Most registries have established mechanisms for data linkage with national administrative datasets or insurance claims datasets and contribute to quality improvement through regular reporting to participating centres. National vascular registries from nations participating in the VASCUNET collaborative AAA projects are largely comprehensive, with high case ascertainment rates and good quality data with internal quality assurance. This provides a template for new registries wishing to join the VASCUNET collaboration and a benchmark for future research. [ABSTRACT FROM AUTHOR]

To determine the peri-operative mortality rate for intact and ruptured abdominal aortic aneurysm (AAA) repair in 10 countries and to compare practice and outcomes over a six year period by age, sex, and geographic location. This VASCUNET study used prospectively collected data from vascular registries in 10 countries on primary repair of intact and ruptured AAAs undertaken between January 2014 and December 2019. The primary outcome was peri-operative death (30 day or in hospital). Logistic regression models were used to estimate the association between peri-operative death, patient characteristics, and type of procedure. Factors associated with the use of endovascular aortic aneurysm repair (EVAR) were also evaluated. The analysis included 50 642 intact and 9 453 ruptured AAA repairs. The proportion of EVARs for intact repairs increased from 63.4% in 2014 to 67.3% in 2016 before falling to 62.3% in 2019 (p <.001), but practice varied between countries. EVAR procedures were more common among older patients (p <.001) and men (p <.001). Overall peri-operative mortality after intact AAA repair was 1.4% (95% confidence interval [CI] 1.3 – 1.5%) and did not change over time. Mortality rates were stable within countries. Among ruptured AAA repairs, the proportion of EVARs increased from 23.7% in 2014 to 35.2% in 2019 (p <.001). The average aortic diameter was 7.8 cm for men and 7.0 cm for women (p <.001). The overall peri-operative mortality rate was 31.3% (95% CI 30.4 – 32.2%); the rates were 36.0% (95% CI 34.9 – 37.2%) for open repair and 19.7% (95% CI 18.2 – 21.3%) for EVAR. This difference and shift to EVAR reduced peri-operative mortality from 32.6% (in 2014) to 28.7% (in 2019). The international practice of intact AAA repair was associated with low mortality rates in registry reported data. There remains variation in the use of EVAR for intact AAAs across countries. Overall peri-operative mortality remains high after ruptured AAA, but an increased use of EVAR has reduced rates over time. [ABSTRACT FROM AUTHOR]

For students with learning disabilities (LD), note taking during lectures and discussions is a difficult task. Many students have difficulties with listening comprehension and written expression, two important skills vital for successful note taking during teacher lectures. Note taking is a cognitively demanding task whereby students must temporarily hold/rehearse incoming verbal lecture information, quickly construct representations into meaningful bits of information that can be recorded, and then transcribe the bits of meaningful information onto paper before the information is lost and before processing any new incoming information. Despite the difficulty of this task, smartpen technology can aid students during note taking by storing verbal lecture information and then syncing it up when students amend their partial notes. This article provides an overview of a smartpen strategy and a guide for teachers to implement this assistive technology in their classroom and improve the note taking of students with LD.

PurposeTo determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.Materials and methodsPatients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.ResultsTwenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.ConclusionsThe combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.

BackgroundIntravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.MethodsIn this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.Findings790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p101 mg × h/L) than in the low AUC group (

Students with learning disabilities have been reported to have difficulty in a number of different executive function processes that affect their academic performance (Singer & Bashir, 1999). Executive function difficulties for students with learning disabilities have been implicated as the reason why these students struggle with complex academic tasks such as reading, writing, and note-taking (Denckla, 2007). This mixed-methods study explored the extent to which a strategic note-taking intervention encouraged more efficient employment of executive function in middle school students with learning disabilities. This paper draws on interviews, students' notes, and pre- and post-intervention assessments to present case studies of three student participants. Results indicate that the strategic note-taking intervention served as a scaffold, opening up new pathways for struggling students to access executive functions and flexibly deploy cognitive strategies. Importantly, "how" each student did so and "what" each student learned about her/himself as a learner in the process were dependent on the specific challenges presented by her/his learning disability. These cases shed light on the potential for cognitive scaffolding to help students actively improve their own executive functioning in complex tasks such as note-taking

For high school students with disabilities, one major component of learning in inclusive content area classes, such as English/language arts (ELA), involves listening to verbal information and recording notes. Learning how to record verbal information in notes is a critical skill for students to succeed in these classes. Therefore, this study randomized 54 students with and without disabilities into experimental and control groups and asked them to record notes in inclusive ELA classes. Students in the experimental group, who were taught the smartpen intervention, scored significantly higher on notes and an achievement measure than control group students. The limitations of the research, implications for future research, and recommendations for teachers are discussed.

BackgroundPopulation pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation.Patients and methodsModel development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model.ResultsModeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02).ConclusionsWhen compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 – 4 mm, 5 – 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p =.001) and FEVAR (2.2%; p =.001) than OSR (4.5%). In standard risk patients with a 0 – 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 – 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 – 4 mm neck length), with comparable midterm survival. For patients with short neck (5 – 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age. [ABSTRACT FROM AUTHOR]

The European Society for Vascular Surgery (ESVS) has developed clinical practice guidelines for the care of patients with aneurysms of the abdominal aorta and iliac arteries in succession to the 2011 and 2019 versions, with the aim of assisting physicians and patients in selecting the best management strategy. The guideline is based on scientific evidence completed with expert opinion on the matter. By summarising and evaluating the best available evidence, recommendations for the evaluation and treatment of patients have been formulated. The recommendations are graded according to a modified European Society of Cardiology grading system, where the strength (class) of each recommendation is graded from I to III and the letters A to C mark the level of evidence. A total of 160 recommendations have been issued on the following topics: Service standards, including surgical volume and training; Epidemiology, diagnosis, and screening; Management of patients with small abdominal aortic aneurysm (AAA), including surveillance, cardiovascular risk reduction, and indication for repair; Elective AAA repair, including operative risk assessment, open and endovascular repair, and early complications; Ruptured and symptomatic AAA, including peri-operative management, such as permissive hypotension and use of aortic occlusion balloon, open and endovascular repair, and early complications, such as abdominal compartment syndrome and colonic ischaemia; Long term outcome and follow up after AAA repair, including graft infection, endoleaks and follow up routines; Management of complex AAA, including open and endovascular repair; Management of iliac artery aneurysm, including indication for repair and open and endovascular repair; and Miscellaneous aortic problems, including mycotic, inflammatory, and saccular aortic aneurysm. In addition, Shared decision making is being addressed, with supporting information for patients, and Unresolved issues are discussed. The ESVS Clinical Practice Guidelines provide the most comprehensive, up to date, and unbiased advice to clinicians and patients on the management of abdominal aorto-iliac artery aneurysms. [ABSTRACT FROM AUTHOR]

For children receiving allogeneic hematopoietic stem cell transplants (HSCTs), the toxicity of the conditioning regimen and graft failure remain challenges. We previously reported that targeted i.v. busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG) decreased toxicity but had a graft failure rate of 21%. To improve the engraftment rate, we replaced ATG with alemtuzumab, a monoclonal Ab targeting CD52. Thirty-five children with malignant and nonmalignant diseases were enrolled in this phase II prospective study. Twelve children had HLA-matched related donors (MRDs), 16 had 10 of 10, and 7 had 9 of 10 HLA allele-matched unrelated donors (MUDs). Thirty-one of 34 evaluable patients (91%) achieved a durable engraftment. All 3 patients who rejected had a nonmalignant disease and received a MUD transplantation (2 mismatched at 1 antigen). Three patients died of a transplantation-related complication (9% ± 5.2%). Seven patients had disease relapse or progression, 2 of whom died. At a median follow-up of 35 months (range, 15-85 months), the event-free survival (EFS) was 61% ± 9.0% and the overall survival (OS) was 78% ± 7.5%. The median time to neutrophil recovery, B cell, and T cell reconstitution were 16 days, 3 months, and 6 months, respectively. At 1 year, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 subsets were 97%, 87%, 100%, and 99%, respectively. Six patients (17% ± 6.6%) developed acute graft-versus-host disease (aGVHD), only 2 of which were >grade II. Two patients (8% ± 5.4%) progressed to chronic GVHD (cGVHD). These results suggest that replacement of rATG with alemtuzumab may improve engraftment as well as decrease cGVHD rates without resulting in delays in immune reconstitution.

This mixed-methods study analysed over 200 interviews from 20 seventh-grade students with learning disabilities (LD). Students were instructed how to use a note-taking intervention during science lectures. The interview analyses were supported by pre- and post-intervention quantitative data. Data suggest that the intervention helped students identify important information; systematised the process of listening to, interpreting and using that information; and offered students a means by which to organise the information they were hearing. A discussion about metacognition and attention explores how these processes altered students' awareness of their own learning, as well as how they equipped students with a new strategy for holding onto and translating information from their science lectures into a useful set of notes. These findings have implications for how theorists conceptualise the relationship between metacognition and attention and how teachers use scaffolding to support the learning of students with LD.

As high-stakes testing, Common Core, and state standards become the new norms in schools, teachers are tasked with helping all students meet specific benchmarks. In conjunction with the influx of more students with disabilities being included in inclusive and general education classrooms where lectures with note-taking comprise a majority of instruction, teachers must find ways to assist all students in their classes, especially students with disabilities. For these students to learn efficiently, note-taking becomes a critical skill for their success. This article addresses the demands placed on students during class lectures, difficulties they experience with note-taking, specific accommodations for students with disabilities, and practical ways in which teachers can help students successfully record notes in content area classes.

The purpose of this exploratory study was to develop and test a strategy to support middle grade students' persuasive writing skills. The sample included 52 eighth-grade students who were either proficient or struggling writers. The students were randomly assigned to either receive training on a graphic organizer designed to scaffold effective persuasive writing (experimental group) or receive training on a strategy to scaffold reading comprehension (control group). Students were posttested on relevant writing and reading skills. Results indicated that, regardless of initial writing skill level, students who were trained in the persuasive writing strategy were able to implement the steps with fidelity and constructed higher quality written essays than students in the control group. Implications and application to middle school language arts classes are discussed.

Cardiovascular disease represents a source of major health problems worldwide, and although medical and technical advances have been achieved, they are still associated with high morbidity and mortality rates. Personalized medicine would benefit from novel tools to better predict individual prognosis and outcomes after intervention. Artificial intelligence (AI) has brought new insights to cardiovascular medicine, especially with the use of machine learning techniques that allow the identification of hidden patterns and complex associations in health data without any a priori assumptions. This review provides an overview on the use of artificial intelligence–based prediction models in vascular diseases, specifically focusing on aortic aneurysm, lower extremity arterial disease, and carotid stenosis. Potential benefits include the development of precision medicine in patients with vascular diseases. In addition, the main challenges that remain to be overcome to integrate artificial intelligence–based predictive models in clinical practice are discussed. [ABSTRACT FROM AUTHOR]

Defining, maintaining, and improving quality is essential to surgical practice. This article utilizes a leading quality assessment model and explores its relevance to the surgical community. National initiatives are discussed with critique of their effectiveness in improving clinical outcomes. Maintaining quality of care during crisis is addressed. [ABSTRACT FROM AUTHOR]

It has been suggested that peri-operative complications after carotid surgery may be higher in women than in men. This assumption may affect the treatment patterns, and it is thus possible that carotid endarterectomy (CEA) is provided to women less often. The aim of the current VASCUNET study was to determine sex related differences in operative risk in routine clinical practice among non-selected patients undergoing carotid revascularisation. Data on CEA and carotid artery stenting (CAS) from 14 vascular registries were collected and amalgamated. Comprehensive data were available for 223 626 carotid artery procedures; these were analysed overall and by country. The primary outcome was any stroke and or death within 30 days of carotid revascularisation. Secondary outcomes were stroke, death, or any major cardiac event or haemorrhage leading to re-operation. Of the procedures, 34.8% were done in women. The proportion of CEA for asymptomatic stenosis compared with symptomatic stenosis was significantly higher among women than men (38.4% vs. 36.9%, p <.001). The proportion of octogenarians was higher among women than men who underwent CEA in both asymptomatic (21.2% vs. 19.9%) and symptomatic patients (24.3% vs. 21.4%). In the unadjusted analysis of symptomatic and asymptomatic patients, there were no significant differences between men and women in the rate of post-operative combined stroke and or death, any major cardiac event, or combined death, stroke, and any major cardiac event after CEA. Also, after stenting for asymptomatic or symptomatic carotid stenosis, there were no significant differences between men and women in the rate of post-operative complications. In adjusted analyses, sex was not significantly associated with any of the end points. Higher age and CAS vs. CEA were independently associated with all four end points. This study confirmed that, in a large registry among non-selected patients, no significant sex related differences were found in peri-operative complication rates after interventions for carotid stenosis. [ABSTRACT FROM AUTHOR]

There is limited information on changes in the patterns of care and outcomes for patients who had vascular procedures after the first wave of the COVID-19 pandemic. The aim of this population based study was to examine the patterns of care and outcomes for vascular lower limb procedures in the UK during the COVID-19 pandemic. Lower limb revascularisations and major amputations performed from January 2019 to April 2021 in the UK and entered in the National Vascular Registry were included in the study. The primary outcome was in hospital post-operative death and secondary outcomes were complications and re-interventions. The study was divided into Pre-pandemic (1 January 2019 – 29 February 2020), Wave 1 (1 March – 30 June 2020), Respite (1 July – 31 October 2020), Wave 2/3 (1 November 2020 – 30 April 2021). The study included 36 938 procedures (7 245 major amputations, 16 712 endovascular, 12 981 open revascularisations), with 15 501 procedures after March 2020, a 27.7% reduction compared with pre-pandemic. The proportion of open surgical procedures performed under general anaesthetic was lower in Wave 1 and after compared with pre-pandemic (76.7% vs. 81.9%, p <.001). Only 4.6% of patients in the cohort had SARS-CoV-2 infection (n = 708), but their in hospital post-operative mortality rate was 25.0% (n = 177), six times higher than patients without SARS-CoV-2 (adjusted odds ratio 5.88; 95% CI 4.80 – 7.21, p <.001). The in hospital mortality rate was higher during the pandemic than pre-pandemic after elective open and endovascular revascularisation (respectively 1.6% vs. 1.1%, p =.033, and 0.9% vs. 0.5%, p =.005) and after major amputations (10.4% during Wave 2/3 vs. 7.7% pre-pandemic, p =.022). There was excess post-operative mortality rate for patients undergoing lower limb vascular procedures during the pandemic, which was associated with SARS-CoV-2 infections. Further research should be conducted on long term outcomes of patients operated on during the COVID-19 pandemic period. [ABSTRACT FROM AUTHOR]

This article provides a synthesis of note-taking research among students with learning disabilities or other high-incidence disabilities. A search of the professional literature between 1980 and 2010 yielded nine intervention studies, which were evaluated either in terms of effect size or percentage of nonoverlapping data. The studies examined three different note-taking techniques used by students during lectures and included 125 students of varying disabilities. Findings revealed that students who used note-taking techniques were effective at increasing scores on measures of achievement and the quality and quantity of notes recorded. Limitations and implications of note-taking techniques for content-area classrooms are discussed. (Contains 2 tables and 2 notes.)

As more secondary students with learning disabilities (LD) enroll in advanced content-area classes and are expected to pass state exams, they are faced with the challenge of mastering difficult concepts and abstract vocabulary while learning content. Once in these classes, students must learn from lectures that move at a quick pace, record accurate and complete notes, and then demonstrate their mastery of the content on tests. This article provides an overview of the challenges faced by students with LD in content-area classes and discusses the problems that students have learning from lectures and recording notes. Further, the article discusses theory and research related to note-taking and presents note-taking interventions that teachers can use to help students improve their note-taking skills, and ultimately, improve their achievement in these classes.

Although teachers today use a variety of teaching methods in content-area classrooms, lecture learning and note-taking still comprise a considerable portion of time in these classes. Unfortunately, most students are poor note-takers, typically recording only about one quarter of lecture notes. Strategic note-taking was developed to assist students during lecture learning and note-taking. In this study, 76 middle school students were assigned to an experimental or control group to assess the effects of strategic note-taking on notes recorded, a delayed recall measure, and a test. The results of multivariate analyses indicated that students who used strategic note-taking recorded significantly more notes and performed better on achievement measures than students in the control group. Limitations and implication for practice are discussed.

For middle school students with learning disabilities (LD), one major component of learning in content area classes, such as science, involves listening to lectures and recording notes. Lecture learning and note-taking are critical skills for students to succeed in these classes. Despite the importance of note-taking skills, no research has been reported on the problems that school-age students with LD encounter when recording notes during science lectures. Using a sample size of 90 middle school students, the performance of students with LD was compared to students with no learning disabilities (NLD). Results found that students with LD performed significantly worse than students with NLD in terms of the type and amount of notes recorded and test performance. (Contains 2 tables and 1 figure.)

While today's teachers use a variety of teaching methods in middle-school science classes, lectures and note-taking still comprise a major portion of students' class time. To be successful in these classes, middle-school students need effective listening and note-taking skills. Students with learning disabilities (LD) are poor note-takers, which negatively impacts their academic performance. This investigation sought to examine the effects of strategic note-taking on the recall and comprehension of middle-school students with LD. Forty students with LD were randomly assigned to either an experimental or a control group. Using strategic note-taking, students in the experimental group were taught to record notes independently while viewing a videotaped science lecture. Students who were taught strategic note-taking scored significantly higher on measures of immediate free recall, long term free recall, comprehension, and number of lecture points and words recorded in their notes than students in a control group who used conventional note-taking. The limitations of the research and implications of this technique for classroom application are discussed. (Contains 3 tables and 2 figures.)

Using a cross-sectional survey, data were collected from 265 first-year college students to determine if parent-student alcohol communication is associated with college drinking or drinking consequences and if this relationship is mediated by students' parental subjective norms, attitudes toward drinking, and perceived risk. Structural equation modeling was used to test hypotheses. Students whose parents talked with them more about the negative effects of alcohol reported more extensive college drinking ([beta] = 0.12, p less than 0.05). Favorable alcohol attitudes were significantly related to both more extensive college drinking ([beta] = 0.49, p less than 0.05) and more drinking consequences ([beta] = 0.39, p less than 0.05). Lower reported perceived risk was significantly related to more drinking consequences ([beta] = -0.24, p less than 0.05). Findings indicate that parental communication regarding the negative effects of alcohol may be ineffective at reducing college drinking or drinking consequences. (Contains 3 tables and 3 figures.)

Teaching children with mild disabilities to read can be a challenging task for even the most seasoned teacher. In order to be successful, teachers need to be knowledgeable about the big five of reading: phonemic awareness, phonics, fluency, vocabulary, and comprehension (National Reading Panel, 2000). While the ultimate goal of reading is comprehension, several of the aforementioned skills must be in place to meet this goal (Tolman, 2005). Despite knowledge of the big five, other skills such as syllabication and structural analysis, subsumed under phonics and vocabulary instruction, are needed in order for children to progress from word-callers to becoming fluent readers who can efficiently comprehend text. (Contains 2 tables and 2 figures.)

Students with mild disabilities have a difficult time recording notes from lectures. Accurate note taking is important because it helps students understand the content from lectures and notes serve as a document for later review. In this article, the author describes what teachers can do before, during, and after the lecture to help students become better note takers.

Students with learning disabilities lack effective note-taking skills for a variety of reasons. Despite the important role that notes play in helping students to understand lecture content information and serving as documents for later review, many students with learning disabilities are simply not effective note-takers. Many of these students record incomplete notes and record fewer notes when compared to nondisabled students. This article will familiarize the reader with research-based note-taking techniques that students can use to improve their learning during lectures.

There is a paucity of research investigating the impact that parents may have on college drinking. In this study, the authors investigated the relationship between students' perceptions of parent approval of drinking and problem drinking occurrence. They conducted a Web-based survey of 265 first-year students living on campus during their second semester. The authors used logistic regression to examine the relationship between students' perceptions of their mothers' and fathers' attitudes toward their drinking, their mothers' and fathers' drinking habits, and problem drinking since they had begun college. Sixty-nine percent of respondents reported experiencing at least 1 drinking problem. Over one third of students perceived that their parents would approve of them drinking occasionally. Students perceiving more parental approval for their drinking were more likely to report at least 1 drinking problem. Student perceptions of parental approval of drinking warrant further investigation as a potentially mutable correlate of problem drinking. (Contains 1 figure and 3 tables.)

Assessed the association between parental monitoring and adolescent alcohol risk. Surveys of adolescents in a managed care setting examined alcohol involvement and forms of parent influence. Frequent monitoring related to less likelihood of being engaged in a variety of alcohol risk behaviors or other risk situations. Choosing to share alcohol related concerns with other adults did not relate as consistently to alcohol risk. (SM)