Single dose v two-dose antenatal anti-D prophylaxis: a randomised controlled trial.

OBJECTIVE: To compare rates of detectability of circulating Rh(D)-immunoglobulin (anti-D) at delivery with single and two-dose antenatal anti-D prophylaxis (RAADP) regimens; to compare compliance with the two regimens. DESIGN: Open label, randomised controlled trial between May 2013 and November 2015. SETTING, PARTICIPANTS: 277 women who attended a tertiary obstetric referral hospital in Perth for antenatal care and were at least 18 years of age, less than 30 weeks pregnant and yet to receive RAADP, Rh(D)-negative (negative antibody screen), and who intended to deliver their baby at the hospital. Exclusion criteria were prior anti-D sensitisation, any contraindication of anti-D administration, and a history of isolated IgA deficiency. INTERVENTIONS: One 1500 IU anti-D dose at 28 weeks of pregnancy (single dose regimen); two doses of 625 IU each at 28 and 34 weeks of pregnancy (two-dose regimen). MAIN OUTCOME MEASURES: The primary outcome was the proportion of women with detectable anti-D levels at delivery; the secondary outcome was compliance with the allocated RAADP regimen. RESULTS: Circulating anti-D was detectable at delivery in a greater proportion of women in the two-dose group (111 of 129, 86%) than in the single dose group (70 of 125, 56%; P < 0.001). Compliance was not significantly different between the single dose (86 of 138, 61%) and two-dose groups (70 of 139, 50%; P = 0.06). CONCLUSIONS: The two-dose RAADP schedule currently recommended in Australia provides better protection against Rh(D) sensitisation than a one-dose regimen. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12613000661774).

Genetic Counselor and Healthcare Interpreter Perspectives on the Role of Interpreters in Cancer Genetic Counseling.

Cancer genetic counseling (CGC) combines psychosocial counseling and genetic education provided by genetic counselors to patients and families who have a history of cancer and are considering or have undergone genetic testing for hereditary cancer syndromes. The quantity and complexity of information provided can be challenging for any patient, but is even more so for those with limited English proficiency (LEP). This exploratory study investigated healthcare interpreters' and genetic counselors' perspectives on the role of interpreters in providing care to LEP patients during CGC. Through a survey of 18 interpreters and conventional content analysis of semi-structured interviews with 11 interpreters and 10 GCs at two California public hospitals, we found that: 1) interpreters viewed their role as patient advocate, cultural broker, and emotional support, not simply a conduit; 2) interpreters were challenged by remote interpretation, lack of genetic knowledge, and the emotional content of encounters; 3) interpreters and GCs held conflicting views of the value of counselors' limited Spanish knowledge; and 4) trust, the foundation of the interpreter-provider dyad, was often lacking. The challenges identified here may result in poor healthcare experiences and outcomes for LEP patients. As genomics becomes more widespread and more LEP patients encounter CGC, the role of healthcare interpreters in facilitating effective communication must be further defined in order to facilitate better working relationships between interpreters and genetic counselors, and optimal communication experiences for patients.

Practice patterns of female urologists in Australia and New Zealand.

OBJECTIVE: To analyse the practice patterns of female urologists in Australia and New Zealand. PARTICIPANTS AND METHODS: An electronic survey was sent to female urologists and urology trainees of the Urological Society of Australia and New Zealand in December 2016, with questions on demographics, practice patterns and views on mentorship. RESULTS: Of 82 recipients of the questionnaire, 60 (73.2%) responded. Of these, 61.7% were aged <40 years, 81.7% were married or in a long-term relationship and 56.7% had children. A total of 67.8% had completed urology training. Of these, most had commenced clinical practice within the preceding 12 years, most had taken no time off in training and most had taken <1 year away from clinical practice. A total of 74.4% practised in a metropolitan area and 42.5% described their practice as being general urology. High or moderate satisfaction levels were reported by 88.1% of respondents and 92.9% intended to retire before the age of 70 years. A total of 17.2% had not had a mentor and 80.7% thought a mentorship scheme would be useful. CONCLUSION: These results provide information on the practice patterns of the increasing number of women urologists in Australia and New Zealand and have the potential to shape workforce and training planning in this region and worldwide.

Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition.

Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry.

Information Mismatch: Cancer Risk Counseling with Diverse Underserved Patients.

As genetics and genomics become part of mainstream Medicine, these advances have the potential to reduce or exacerbate health disparities. Gaps in effective communication (where all parties share the same meaning) are widely recognized as a major contributor to health disparities. The purpose of this study was to examine GC-patient communication in real time, to assess its effectiveness from the patient perspective, and then to pilot intervention strategies to improve the communication. We observed 64 English-, 35 Spanish- and 25 Chinese-speaking (n = 124) public hospital patients and 10 GCs in 170 GC appointments, and interviewed 49 patients who were offered testing using the audio recordings to stimulate recall and probe specific aspects of the communication. Data analyses were conducted using grounded theory methods and revealed a fundamental mismatch between the information provided by GCs and the information desired and meaningful to patients. Several components of the communication that contributed to this mismatch and often resulted in ineffective communication included: (1) too much information; (2) complex terminology and conceptually difficult presentation of information; (3) information perceived as not relevant by the patient; (4) unintentional inhibition of patient engagement and question-asking; (5) vague discussions of screening and prevention recommendations. Our findings indicate a need to transform the standard model of genetic counseling communication using evidence-based principles and strategies from other fields of Medicine. The high rates of limited health literacy in the US, increasing access of diverse populations to genetic services, and growing complexity of genetic information have created a perfect storm. If not directly addressed, this convergence is likely to exacerbate health disparities in the genomic age.

High-throughput platform for real-time monitoring of biological processes by multicolor single-molecule fluorescence.

Zero-mode waveguides provide a powerful technology for studying single-molecule real-time dynamics of biological systems at physiological ligand concentrations. We customized a commercial zero-mode waveguide-based DNA sequencer for use as a versatile instrument for single-molecule fluorescence detection and showed that the system provides long fluorophore lifetimes with good signal to noise and low spectral cross-talk. We then used a ribosomal translation assay to show real-time fluidic delivery during data acquisition, showing it is possible to follow the conformation and composition of thousands of single biomolecules simultaneously through four spectral channels. This instrument allows high-throughput multiplexed dynamics of single-molecule biological processes over long timescales. The instrumentation presented here has broad applications to single-molecule studies of biological systems and is easily accessible to the biophysical community.

Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS: We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). CONCLUSIONS: We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

A divergent approach to the synthesis of iGb3 sugar and lipid analogues via a lactosyl 2-azido-sphingosine intermediate.

Isoglobotrihexosylceramide (iGb3, 1) is an immunomodulatory glycolipid that binds to CD1d and is presented to the T-cell receptor (TCR) of invariant natural killer T (iNKT) cells. To investigate how modifications to the lipid tail or terminal sugar residue of iGb3 influence iNKT cell activity, we developed an efficient and divergent synthetic route that provided access to both sugar and lipid iGb3 analogues which utilised a lactosyl 2-azido-sphingosine derivative as a common intermediate. In this way, iGb3 (1) and the unprecedented analogues 6'''-deoxy-iGb3-sphingosine 2, 6'''-deoxy-iGb3-sphinganine 3, C12 N-acyl iGb3 4 and C20:2 N-acyl iGb3 5 were prepared so that key structure-activity relationships can be explored.

The interpersonal shame inventory for Asian Americans: scale development and psychometric properties.

This article reports the development and psychometric properties of the Interpersonal Shame Inventory (ISI), a culturally salient and clinically relevant measure of interpersonal shame for Asian Americans. Across 4 studies involving Asian American college students, the authors provided evidence for this new measure's validity and reliability. Exploratory factor analyses and confirmatory factor analyses provided support for a model with 2 correlated factors: external shame (arising from concerns about others' negative evaluations) and family shame (arising from perceptions that one has brought shame to one's family), corresponding to 2 subscales: ISI-E and ISI-F, respectively. Evidence for criterion-related, concurrent, discriminant, and incremental validity was demonstrated by testing the associations between external shame and family shame and immigration/international status, generic state shame, face concerns, thwarted belongingness, perceived burdensomeness, self-esteem, depressive symptoms, and suicide ideation. External shame and family shame also exhibited differential relations with other variables. Mediation findings were consistent with a model in which family shame mediated the effects of thwarted belongingness on suicide ideation. Further, the ISI subscales demonstrated high alpha coefficients and test-retest reliability. These findings are discussed in light of the conceptual, methodological, and clinical contributions of the ISI.

Species-specific activity of glycolipid ligands for invariant NKT cells.

The immunomodulatory glycolipid α-galactosylceramide (α-GalCer) binds to CD1d and exhibits potent activity as a ligand for invariant CD1d-restricted natural killer-like T cells (iNKT cells). Structural analogues of α-GalCer have been synthesised to determine which components are required for CD1d presentation and iNKT cell activation, however, to date the importance of the phytosphingosine 4-hydroxyl for iNKT cell activation has been disputed. To clarify this, we synthesised two 4-deoxy α-GalCer analogues (sphinganine and sphingosine) and investigated their ability to activate murine and human iNKT cells. Analysis revealed that the analogues possessed comparable activity to α-GalCer in stimulating murine iNKT cells, but were severely compromised in their ability to stimulate human iNKT cells. Here we determined that species-specific glycolipid activity was due to a lack of recognition of the analogues by the T-cell receptors on human iNKT cells rather than insufficient presentation of the analogues on human CD1d molecules. From these results we suggest that glycolipids developed for potent iNKT cell activity in humans should contain a phytosphingosine base.

Streptococcus intermedius causing cellulitis of the penile shaft complicated with abscess formation and rupture after dry humping sex.

Penile cellulitis with abscess formation then rupture is an extremely rare presentation. This is a case report of a penile shaft abscess caused by Streptococcus intermedius after 'dry humping' sexual activities. A 34-year-old healthy man was presented with painful penile swelling for 3 weeks after initial 'dry humping' and later penovaginal intercourse. He was admitted to the hospital for intravenous antibiotics treatment, but a penile abscess was developed and ruptured within 24 hours. Urgent penile exploration revealed localised abscess and S. intermedius was isolated. The wound healed by secondary intention. However, his admission was complicated by acute kidney injury, probably due to vancomycin. Therefore, longer inpatient supportive care was required before discharge. Given this severe complication of primary penile cutaneous infection by S. intermedius, our case would raise awareness of this normal flora in abscess development at the male genital region, and the importance for the patient seeking prompt medical advice and physicians administrating appropriate antibiotics.

The NKT cell TCR repertoire can accommodate structural modifications to the lipid and orientation of the terminal carbohydrate of iGb3.

Isoglobotrihexosylceramide (iGb3) is a known NKT cell agonist, however the specific interactions required to trigger NKT cell TCR activation in response to this mammalian glycolipid are not fully understood. Here we report the synthesis of 1,3-ß-Gal-LacCer (ßG-iGb3) that displays a ß-linked terminal sugar. ßG-iGb3 activated NKT cells to a similar extent as iGb3 with a terminal α-linkage, indicating that the conformation of the terminal sugar residue of iGb3 is not essential to facilitate NKT cell TCR recognition. In addition, the immunological activity of four recently described iGb3 analogues with modifications to their terminal sugar or lipid backbone were also investigated. These iGb3 analogues all induced NKT cell proliferation, with IL-13 the predominate cytokine detected. This highlights the ability of the NKT cell TCR to accommodate variations in iGb3-based glycolipids and suggests that undiscovered NKT cell ligands may exist within the lacto-series of mammalian glycosphingolipids.

Multi-Planar VMAT Plans for High-Grade Glioma and Glioblastoma Targeting the Hypothalamic-Pituitary Axis Sparing.

BACKGROUND: This study aimed to identify the better arc configuration of volumetric modulated arc therapy (VMAT) for high-grade glioma and glioblastoma, focusing on a dose reduction to the hypothalamic-pituitary axis through an analysis of dose-volumetric parameters, as well as a correlation analysis between the planned target volume (PTV) to organs at risk (OAR) distance and the radiation dose. METHOD: Twenty-four patients with 9 high-grade glioma and 15 glioblastomas were included in this study. Identical CT, MRI and structure sets of each patient were used for coplanar VMAT (CO-VMAT), dual planar VMAT (DP-VMAT) and multi-planar VMAT (MP-VMAT) planning. The dose constraints adhered to the RTOG0825 and RTOG9006 protocols. The dose-volumetric parameters of each plan were collected for statistical analysis. Correlation analyses were performed between radiation dose and PTV-OARs distance. RESULTS: The DP-VMAT and MP-VMAT achieved a significant dose reduction to most nearby OARs when compared to CO-VMAT, without compromising the dose to PTV, plan homogeneity and conformity. For centrally located OARs, including the hypothalamus, pituitary, brain stem and optic chiasm, the dose reductions ranged from 2.65 Gy to 3.91 Gy (p < 0.001) in DP-VMAT and from 2.57 Gy to 4 Gy (p < 0.001) in MP-VMAT. Similar dose reduction effects were achieved for contralaterally located OARs, including the hippocampus, optic nerve, lens and retina, ranging from 1.06 Gy to 4.37 Gy in DP-VMAT and from 0.54 Gy to 3.39 Gy in MP-VMAT. For ipsilaterally located OARs, DP-VMAT achieved a significant dose reduction of 1.75 Gy to Dmax for the optic nerve. In the correlation analysis, DP-VMAT and MP-VMAT showed significant dose reductions to centrally located OARs when the PTV-OAR distance was less than 4 cm. In particular, DP-VMAT offered better sparing to the optic chiasm when it was located less than 2 cm from the PTV than that of MP-VMAT and CO-VMAT. DP-VMAT and MP-VMAT also showed better sparing to the contralateral hippocampus and retina when they were located 3-8 cm from the PTV. CONCLUSION: The proposed DP-VMAT and MP-VMAT demonstrated significant dose reductions to centrally located and contralateral OARs and maintained the high plan qualities to PTV with good homogeneity and conformity when compared to CO-VMAT for high-grade glioma and glioblastoma. The benefit in choosing DP-VMAT and MP-VMAT over CO-VMAT was substantial when the PTV was located near the hypothalamus, pituitary, optic chiasm, contralateral hippocampus and contralateral retina.

Methyl 6-azido-6-de-oxy-α-d-galactoside.

The structure of the title compound, C(7)H(13)N(3)O(5), was solved using data from a multiple fragment crystal. The galactoside ring adopts a (4)C(1) chair conformation. In the crystal, the molecules are linked by strong O-H⋯O hydrogen bonds, which build linkages around the screw axis of the cell in a similar way to the iodo analogue. These C-5 and C-6 packing motifs expand to R(2) (2)(10), C(2) (2)(7) and C(2) (2) (2)(8) motifs, as found in closely related compounds.

Preclinical Evaluation of Gilteritinib on NPM1-ALK-Driven Anaplastic Large Cell Lymphoma Cells.

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0-G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies. IMPLICATIONS: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK-driven ALCL cells and pave a path for developing future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/913/F1.large.jpg.

Modified VMAT Plans for Locally Advanced Centrally Located Non-Small Cell Lung Cancer (NSCLC).

OBJECTIVES: This study aimed to find the optimal radiotherapy VMAT plans, that achieved high conformity and homogeneity to the planned target volume (PTV), and minimize the dose to nearby organs at risk including the non-PTV lung, heart and oesophagus for patients with centrally located non-small Cell Lung Cancer. METHODS: A total of 18 patients who were treated for stage III centrally located non-small Cell Lung Cancer were selected retrospectively for this study. Identical CT datasets, 4D CT and structure dataset were used for radiotherapy planning based on single-planar VMAT (SP-VMAT), dual-planar VMAT (DP-VMAT) and Hybrid VMAT (H-VMAT). For SP-VMAT, one full arc and two half arcs were created on single-plane with couch at 0°. For DP-VMAT, one full arc was created with couch at 0°, and two half arcs with couch rotation of 330° or 30°. For H-VMAT, anterior-posterior opposing fixed beam and two half arcs were planned at couch at 0°. Dose constraints were adhered to the RTOG0617. Dose volumetric parameters were collected for statistical analysis. RESULTS: There were no significant differences for the PTV, HI, CI between the SP-VMAT, DP-VMAT and H-VMAT. For the non-PTV lungs, Dmean, V20, V10, V5, D1500 and D1000 were significantly lower (2.05 Gy, 6.47%, 15.89%, 11.66% 4.17 Gy and 5.47 Gy respectively) in H-VMAT than that of SP-VMAT (all p < 0.001). For the oesophagus, Dmax, Dmean, V30 and V18.8 of H-VMAT were 0.08 Gy, 1.73 Gy, 5.54% and 7.17% lower than that of the SP-VMAT plan. For the heart, Dmean, V34, V28, V20 and V10 of DP-VMAT were lower than that of SP-VMAT by 1.45 Gy, 0.65%, 1.74%, 4.8% and 7.11% respectively. CONCLUSION: The proposed H-VMAT showed more favourable plan quality than the SP-VMAT for centrally located stage III NSCLC, in particular for non-PTV lungs and the oesophagus. It will benefit patients, especially those who planned for immunotherapy (Durvalumab) after standard chemo-irradiation. The proposed DP-VMAT plan showed significant dose reduction to the heart when compared to the H-VMAT plan.

Cystectomy in patients with spinal cord injury: indications and long-term outcomes.

PURPOSE: We evaluated indications and outcomes of cystectomy in patients with spinal cord injury in a urology unit attached to a statewide spinal cord injury service. MATERIALS AND METHODS: We performed a review of all patients with spinal cord injury in our database who underwent cystectomy between 1997 and 2008. Demographic, pathological and perioperative data were collected. Oncological outcomes were documented for those with malignant indications while patient satisfaction was recorded using the Patient Global Impression of Improvement scale for all patients. RESULTS: Of 2,569 acute spinal cord injury presentations there were 14 patients who underwent cystectomy. Mean patient age was 53 years (range 39 to 72). Of the 14 patients 9 had malignant disease and 5 had benign indications for cystectomy. Overall mean followup was 48 months (median 30.8). Cumulative survival in the malignant cohort was 66.7% with a 33.3% recurrence rate resulting in death. All survivors remained disease-free at a mean of 49 months (median 31). Mean Patient Global Impression of Improvement score was 3 (range 1-very much better to 7-very much worse). In the nonmalignant cohort mean followup was 75 months (median 77). The overall Patient Global Impression of Improvement score in this group was 2.4, suggesting overall positive patient satisfaction. CONCLUSIONS: In patients with spinal cord injury cystectomy is performed almost as often for nonmalignant as for malignant indications. Our data support a more aggressive presentation of cancer with a different pathological profile but not survival compared to normal populations. Centers treating patients with spinal cord injury should consider a lower threshold for the surgical management of bladder cancer where appropriate, especially considering that morbidity, satisfaction and outcome do not appear to be compromised in patients with spinal cord injury.

Methyl 6-de-oxy-6-iodo-α-d-galactoside.

In the crystal of the title compound, C(7)H(13)IO(5), the molecules are linked by O-H⋯O hydrogen bonds, which build linkages around one screw axis of the cell. These C(5) and C(6) packing motifs expand to R(2) (2)(10) and C(2) (2)(11) motifs and are similar to those found for closely related compounds. The galactoside ring has a (1)C(4) chair conformation.

Aging of cerebral white matter: a review of MRI findings.

BACKGROUND: Cerebral aging is a complex and heterogeneous process that is associated with a high degree of inter-individual variability. Structural magnetic resonance imaging (MRI) can be used to identify and quantify non-disease-related aging of the cerebral white matter. METHODS: The present article reviews the findings from several MRI techniques, including morphometric approaches, study of white matter hyperintensities, diffusion tensor imaging, and magnetization transfer imaging, that have been used to examine aging of the cerebral white matter. Furthermore, the relationship of MRI indices of white matter integrity to age-related cognitive declines is reported. RESULTS: A general pattern of age-related preservation and decline emerges indicating that the prefrontal white matter is most susceptible to the influence of age. Studies that combine MRI with cognitive measures suggest that such age-related reductions in white matter integrity may produce a disconnection state that underlies some of the age-related performance declines in age-sensitive cognitive domains. CONCLUSIONS: White matter aging may contribute to a disconnection state that is associated with declines in episodic memory, executive functions, and information processing speed.