The correlation between carotid artery Doppler and stroke volume during central blood volume loss and resuscitation.

BACKGROUND: Using peripheral arteries to infer central hemodynamics is common among hemodynamic monitors. Doppler ultrasound of the common carotid artery has been used in this manner with conflicting results. We investigated the relationship between changing common carotid artery Doppler measures and stroke volume (SV), hypothesizing that more consecutively-averaged cardiac cycles would improve SV-carotid Doppler correlation. METHODS: Twenty-seven healthy volunteers were recruited and studied in a physiology laboratory. Carotid artery Doppler pulse was measured with a wearable, wireless ultrasound during central hypovolemia and resuscitation induced by a stepped lower body negative pressure protocol. The change in maximum velocity time integral (VTI) and corrected flow time of the carotid artery (ccFT) were compared with changing SV using repeated measures correlation. RESULTS: In total, 73,431 cardiac cycles were compared across 27 subjects. There was a strong linear correlation between changing SV and carotid Doppler measures during simulated hemorrhage (repeated-measures linear correlation [Rrm ]=0.91 for VTI; 0.88 for ccFT). This relationship improved with larger numbers of consecutively-averaged cardiac cycles. For ccFT, beyond four consecutively-averaged cardiac cycles the correlation coefficient remained strong (i.e., Rrm of at least 0.80). For VTI, the correlation coefficient with SV was strong for any number of averaged cardiac cycles. For both ccFT and VTI, Rrm remained stable around 25 consecutively-averaged cardiac cycles. CONCLUSIONS: There was a strong linear correlation between changing SV and carotid Doppler measures during central blood volume loss. The strength of this relationship was dependent upon the number of consecutively-averaged cardiac cycles.

Genetic architecture of the structural connectome.

Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function.

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation.

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Case-control virtual histology elucidates cell types associated with cortical thickness differences in Alzheimer's disease.

Many neuropsychiatric disorders are characterised by altered cortical thickness, but the cell types underlying these changes remain largely unknown. Virtual histology (VH) approaches map regional patterns of gene expression with regional patterns of MRI-derived phenotypes, such as cortical thickness, to identify cell types associated with case-control differences in those MRI measures. However, this method does not incorporate valuable information of case-control differences in cell type abundance. We developed a novel method, termed case-control virtual histology (CCVH), and applied it to Alzheimer's disease (AD) and dementia cohorts. Leveraging a multi-region gene expression dataset of AD cases (n = 40) and controls (n = 20), we quantified AD case-control differential expression of cell type-specific markers across 13 brain regions. We then correlated these expression effects with MRI-derived AD case-control cortical thickness differences across the same regions. Cell types with spatially concordant AD-related effects were identified through resampling marker correlation coefficients. Among regions thinner in AD, gene expression patterns identified by CCVH suggested fewer excitatory and inhibitory neurons, and greater proportions of astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells in AD cases vs. controls. In contrast, original VH identified expression patterns suggesting that excitatory but not inhibitory neuron abundance was associated with thinner cortex in AD, despite the fact that both types of neurons are known to be lost in the disorder. Compared to original VH, cell types identified through CCVH are more likely to directly underlie cortical thickness differences in AD. Sensitivity analyses suggest our results are largely robust to specific analysis choices, like numbers of cell type-specific marker genes used and background gene sets used to construct null models. As more multi-region brain expression datasets become available, CCVH will be useful for identifying the cellular correlates of cortical thickness across neuropsychiatric illnesses.

The Correlation between Carotid Artery Corrected Flow Time and Velocity Time Integral during Central Blood Volume Loss and Resuscitation.

Background: Doppler ultrasound of the common carotid artery is used to infer central hemodynamics. For example, change in the common carotid artery corrected flow time (ccFT) and velocity time integral (VTI) are proposed surrogates of changing stroke volume. However, conflicting data exist which may be due to inadequate beat sample size and measurement variability - both intrinsic to handheld systems. In this brief communication, we determined the correlation between changing ccFT and carotid VTI during progressively severe central blood volume loss and resuscitation. Methods: Measurements were obtained through a novel, wireless, wearable Doppler ultrasound system. Sixteen participants (ages of 18-40 years with no previous medical history) were studied across 25 lower body-negative pressure protocols. Relationships were assessed using repeated-measures correlation regression models. Results: In total, 33,110 cardiac cycles comprise this analysis; repeated-measures correlation showed a strong, linear relationship between ccFT and VTI. The strength of the ccFT-VTI relationship was dependent on the number of consecutively averaged cardiac cycles (R1 cycle = 0.70, R2 cycles = 0.74, and R10 cycles = 0.81). Conclusions: These results positively support future clinical investigations employing common carotid artery Doppler as a surrogate for central hemodynamics.

Longitudinal Study of Psychosocial Outcomes Following Surgery in Women with Unilateral Nonhereditary Breast Cancer.

INTRODUCTION: Rates of bilateral mastectomy are rising in women with unilateral, nonhereditary breast cancer. We aim to characterize how psychosocial outcomes evolve after breast cancer surgery. PATIENTS AND METHODS: We performed a prospective cohort study of women with unilateral, sporadic stage 0-III breast cancer at University Health Network in Toronto, Canada between 2014 and 2017. Women completed validated psychosocial questionnaires (BREAST-Q, Impact of Event Scale, Hospital Anxiety & Depression Scale) preoperatively, and at 6 and 12 months following surgery. Change in psychosocial scores was assessed between surgical groups using linear mixed models, controlling for age, stage, and adjuvant treatments. P < .05 were significant. RESULTS: A total of 475 women underwent unilateral lumpectomy (42.5%), unilateral mastectomy (38.3%), and bilateral mastectomy (19.2%). There was a significant interaction (P < .0001) between procedure and time for breast satisfaction, psychosocial and physical well-being. Women having unilateral lumpectomy had higher breast satisfaction and psychosocial well-being scores at 6 and 12 months after surgery compared with either unilateral or bilateral mastectomy, with no difference between the latter two groups. Physical well-being declined in all groups over time; scores were not better in women having bilateral mastectomy. While sexual well-being scores remained stable in the unilateral lumpectomy group, scores declined similarly in both unilateral and bilateral mastectomy groups over time. Cancer-related distress, anxiety, and depression scores declined significantly after surgery, regardless of surgical procedure (P < .001). CONCLUSIONS: Psychosocial outcomes are not improved with contralateral prophylactic mastectomy in women with unilateral breast cancer. Our data may inform women considering contralateral prophylactic mastectomy.

Preconsultation Educational Group Intervention Can Address the Knowledge Gap in Postmastectomy Breast Reconstruction.

BACKGROUND: Whether to undergo postmastectomy breast reconstruction (PMBR) is a challenging, preference-sensitive decision. It is therefore paramount to optimize decision quality through ensuring patients' knowledge and aligning treatments with their personal preferences. This study assessed the effects of a preconsultation educational group intervention (PEGI) on patient knowledge, state-trait anxiety, and decisional conflict (patient uncertainty in decision making) during the decision-making process. METHODS: This phase 3 randomized controlled trial assessed effects of a PEGI in women without active breast cancer undergoing delayed PMBR, or prophylactic mastectomy with immediate PMBR. Both groups underwent routine education before consultation. In addition, the intervention group underwent a PEGI composed of presentations from a plastic surgeon and nurse, a value clarification exercise, and shared experiences from PMBR patients before the consultation with the plastic surgeon. Before and 1-week after consultation, outcome measures were assessed using the Decisional Conflict Scale, State-Trait Anxiety Inventory, and the BREAST-Q. RESULTS: Of the 219 women deemed eligible, a total of 156 women were recruited and randomized. Treatment fidelity was 96% and retention was 88%. At baseline, there were no significant differences in terms of demographic or clinical status, knowledge, state-trait anxiety, and decisional conflict. Patient knowledge about PMBR improved in both groups; however, the degree of knowledge attainment was significantly greater in the PEGI group (24.5% improvement in the intervention group compared with 13.5% in the routine education group, P < 0.001). The reduction in decisional conflict from baseline to follow-up was greater in the intervention group compared with the routine education; however, the difference only approached significance (P = 0.09). CONCLUSIONS: The provision of a preconsultation educational group intervention has been shown to significantly close the knowledge gap on PMBR in patients seeking delayed breast reconstruction or prophylactic mastectomy with immediate breast reconstruction compared with routine education alone.

Contralateral prophylactic mastectomy at the time of delayed microvascular breast reconstruction adversely affects patient-reported outcomes: A retrospective cohort study.

PURPOSE: An increasing number of women with unilateral breast cancer are seeking bilateral mastectomies and reconstruction. At our centre, many women who have undergone previous unilateral therapeutic mastectomy request contralateral prophylactic mastectomy (CPM) at the time of delayed reconstruction. These mixed timing reconstructions are particularly challenging as patients have an immediate reconstruction on one side and delayed reconstruction on the other, which may result in asymmetry. This retrospective cohort study evaluates patient-reported satisfaction following mixed timing breast reconstruction and compares them to unilateral delayed reconstruction. METHODS: One hundred and forty-one patients who underwent successful deep inferior epigastric artery perforator (DIEP) flap breast reconstruction and completed baseline and 12-month BREAST-Qs were included in the study. Patient-reported outcomes following bilateral mixed timing reconstruction (n = 56) were compared to those of unilateral delayed reconstruction (UDR) without CPM (n = 85). RESULTS: Women who sought CPM were significantly younger and had lower annual incomes when compared with those who underwent unilateral reconstruction. Mixed timing reconstruction was associated with significantly lower levels of breast satisfaction and psychosocial function as compared to UDR at 12 months post-operatively. BREAST-Q scores (18 months) were available for 75 patients in the cohort and indicated that this decreased breast satisfaction and psychosocial impairment was sustained in the longer-term. CONCLUSIONS: Patients who seek CPM at the time of delayed reconstruction should be advised that this is associated with lower levels of breast satisfaction and psychosocial well-being as compared to unilateral delayed breast reconstruction.

Predictors of uptake of contralateral prophylactic mastectomy in women with nonhereditary breast cancer.

BACKGROUND: The rates of contralateral prophylactic mastectomy (CPM) are increasing in women with breast cancer. Previous retrospective research has examined clinical and demographic predictors of the uptake of CPM. However, to the authors' knowledge, there has been very little prospective research to date that has examined psychosocial functioning prior to breast cancer surgery to determine whether psychosocial functioning predicts uptake of CPM. The current study was conducted to evaluate demographic, clinical, and psychosocial predictors of the uptake of CPM in women with unilateral breast cancer without a BRCA1 or BRCA2 mutation. METHODS: Women with unilateral non-BRCA-associated breast cancer completed questionnaires prior to undergoing breast cancer surgery. Participants completed demographic and psychosocial questionnaires assessing anxiety, depression, cancer-related distress, optimism/pessimism, breast satisfaction, and quality of life. Pathological and surgical data were collected from medical charts. RESULTS: A total of 506 women consented to participate, 112 of whom (22.1%) elected to undergo CPM. Age was found to be a significant predictor of CPM, with younger women found to be significantly more likely to undergo CPM compared with older women (P < .0001). The rate of CPM was significantly higher in women with noninvasive breast cancer compared with those with invasive breast cancer (P < .0001). Women who elected to undergo CPM had lower levels of presurgical breast satisfaction (P = .01) and optimism (P = .05) compared with women who did not undergo CPM. CONCLUSIONS: Psychosocial functioning at the time of breast cancer surgery decision making impacts decisions related to CPM. Women who have lower levels of breast satisfaction (body image) and optimism are more likely to elect to undergo CPM. It is important for health care providers to take psychosocial functioning into consideration when discussing surgical options.

Psychosocial Functioning in Women with Early Breast Cancer Treated with Breast Surgery With or Without Immediate Breast Reconstruction.

PURPOSE: To compare psychosocial function outcomes in early breast cancer patients treated with breast-conserving surgery (BCS), mastectomy alone (MA), and mastectomy with immediate breast reconstruction (IBR) at 1 year after surgery. METHODS: Early-stage (stage 0-2) breast cancer patients treated with BCS, MA, and IBR at the University Health Network, Toronto, Ontario, Canada between May 1 2015 and July 31 2016 were prospectively enrolled. Their changes in psychosocial functioning from baseline to 12 months following surgery were compared by using the BREAST-Q, Hospital Anxiety and Depression Scale, and Impact of Event Scale with ANOVA and linear regression. RESULTS: There were 303 early-stage breast cancer patients: 155 underwent BCS, 78 MA, and 70 IBR. After multivariable regression accounting for age, baseline score, income, education, receipt of chemoradiation or hormonal therapy, ethnicity, cancer stage, and unilateral versus bilateral surgery, breast satisfaction was highest in BCS (72.1, SD 19.6), followed by IBR (60.0, SD 18.0), and MA (49.9, SD 78.0) at 12 months, p < 0.001. Immediate breast reconstruction had similar psychosocial well-being (69.9, SD 20.6) compared with BCS (78.5, SD 20.6), p = 0.07. Sexual and chest physical well-being were similar between IBR, BCS, and MA, p > 0.05. CONCLUSIONS: Our study found that in a multidisciplinary breast cancer centre where all three breast ablative and reconstruction options are available to early breast cancer patients, either BCS or IBR can be used to provide patients with a higher degree of satisfaction and psychosocial well-being compared with MA in the long-term.

Indications and Controversies for Abdominally-Based Complete Autologous Tissue Breast Reconstruction.

This article reviews the indications and controversies in abdominally based autologous breast reconstruction. The evidence regarding these indications and controversies will be appraised and summarized. Finally, we will provide a summary of our approach and technique for the patient undergoing autologous breast reconstruction using abdominally based free flaps.