Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis.

GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a-/- mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 × 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS-the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.

Prediction of breast cancer-related lymphedema by dermal backflow detected with near-infrared fluorescence lymphatic imaging.

PURPOSE: Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%-10% increase in arm volume, typically measured no earlier than 3-6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL. METHODS: In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4-8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI. RESULTS: By 18 months after RT, 30 of 42 study subjects (71%) developed mild-moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by "dermal backflow" of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL. CONCLUSION: BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes.

Virtual clinical trial to compare cancer detection using combinations of 2D mammography, digital breast tomosynthesis and synthetic 2D imaging.

OBJECTIVES: This study was designed to compare the detection of subtle lesions (calcification clusters or masses) when using the combination of digital breast tomosynthesis (DBT) and synthetic mammography (SM) with digital mammography (DM) alone or combined with DBT. METHODS: A set of 166 cases without cancer was acquired on a DBT mammography system. Realistic subtle calcification clusters and masses in the DM images and DBT planes were digitally inserted into 104 of the acquired cases. Three study arms were created: DM alone, DM with DBT and SM with DBT. Five mammographic readers located the centre of any lesion within the images that should be recalled for further investigation and graded their suspiciousness. A JAFROC figure of merit (FoM) and lesion detection fraction (LDF) were calculated for each study arm. The visibility of the lesions in the DBT images was compared with SM and DM images. RESULTS: For calcification clusters, there were no significant differences (p > 0.075) in FoM or LDF. For masses, the FoM and LDF were significantly improved in the arms using DBT compared to DM alone (p < 0.001). On average, both calcification clusters and masses were more visible on DBT than on DM and SM images. CONCLUSIONS: This study demonstrated that masses were detected better with DBT than with DM alone and there was no significant difference (p = 0.075) in LDF between DM&DBT and SM&DBT for calcifications clusters. Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses. KEY POINTS: • The detection of masses was significantly better using DBT than with digital mammography alone. • The detection of calcification clusters was not significantly different between digital mammography and synthetic 2D images combined with tomosynthesis. • Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses for the imaging technology used.

Topographic Evolution of Anterior Cerebral Artery Infarction and Its Impact on Motor Impairment.

INTRODUCTION: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. METHODS: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. RESULTS: Forty-seven patients with a median age of 77.5 (interquartile range 68.0-84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in <50% of patients and contribution of M1 fiber tracts to the motor deficit was reduced (M1-10.2%, SMA-61.0%, PMdv-28.8%). We confirmed our findings using publicly available high-resolution templates created from Human Connectome Project data. This also showed a reduction in involvement of M1 fiber tracts on initial perfusion imaging (33%) compared to MRI at a median time of 7 days poststroke (11%). CONCLUSION: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Anterior Cerebral Artery Stroke: Role of Collateral Systems on Infarct Topography.

Background and Purpose: The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches. Methods: Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied. Results: Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0­84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses. Conclusions: Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.

Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring. Clinical Trial Registration: NCT04457596 (ClinicalTrials.gov).

Pupillary response: cognitive effort for breast cancer survivors.

PURPOSE: The purpose of this cross-sectional comparative pilot study was to evaluate cognitive effort, indexed by pupillary response (PR), for breast cancer survivors (BCS) with complaints of cognitive dysfunction following chemotherapy. STUDY AIMS: Compare the cognitive effort employed by BCS to healthy controls (HC) during neuropsychological tests (NPT) for memory, sustained attention, verbal fluency, visuospatial ability, processing speed and executive function; and Investigate the relationship between PR-indexed cognitive effort and participants' self-report of cognitive function. METHODS: Self-report of cognitive function was collected from 23 BCS and 23 HC. PR was measured during NPT. Independent two-sample t tests or Wilcoxon rank sum tests were used to compare group scores. Between-group effect size (Cohen's d) was calculated for each outcome. Correlation between mean self-report scores and PR values, as well as 95% confidence intervals, was calculated. RESULTS: No group differences were demonstrated for NPT performance. BCS reported more issues with cognitive function than HC (p < .0001). A group effect for BCS was seen with PR-indexed cognitive effort for components of most NPT (p < .05). PR was correlated with most self-report measures of cognitive function (r = 0.33-0.45). CONCLUSIONS: PR sensitivity to cognitive effort across a variety of NPT and correlation with self-report of cognitive function was demonstrated. The portability, affordability, and "real-time" aspects of PR are attractive for potential use in the clinic setting to assess cognitive function. A larger study is needed to confirm these results. Prospective investigation of PR in BCS is needed to demonstrate sensitivity to cognitive function changes over time.

Qigong intervention for breast cancer survivors with complaints of decreased cognitive function.

PURPOSE: The purpose of this pilot study was to evaluate the feasibility of an 8-week Qigong intervention to improve objectively and subjectively assessed cognitive function in breast cancer survivors who were 2 months to 8 years post completion of chemotherapy and radiation therapy. METHODS: A randomized, single-blind, three-arm intervention pilot was conducted to compare Qigong to gentle exercise and survivorship support. Feasibility was measured by recruitment, group session attendance, and adherence to home practice for the two exercise groups. Changes in self-report and objectively measured cognitive function were compared between the three groups from baseline (T1) to completion of the intervention (T2) and 4 weeks post intervention (T3). RESULTS: Fifty participants consented (83% of desired sample) with an overall attrition rate of 28%. Attrition was highest for the gentle exercise group (50%). Group attendance adherence ranged from 44 to 67%. The a priori established rate of 75% weekly attendance was not achieved, nor was the goal of 75% adherence to home practice for the two exercise groups (7 to 41%). Self-report of cognitive function improved most for the Qigong group (p = .01). Improvement was demonstrated for the Trail Making A (gentle exercise, p = .007) and F-A-S verbal fluency (support group, p = .02) tests. Qigong participants reported the most reduction of distress (p = .02). CONCLUSIONS: The study results suggest that mindfulness-based exercise may be superior to gentle exercise alone or survivorship support for improving self-report of cognitive function and distress after treatment for breast cancer. The mindfulness component may enhance the positive impact of exercise on cognitive function.

Current Therapeutic Approaches to DCIS.

Treatment for ductal carcinoma in-situ (DCIS) has historically been extrapolated from studies of invasive breast cancer. Accepted local therapy approaches range from small local excisions, with or without radiation, to bilateral mastectomies. Systemic treatment with endocrine therapy is often recommended for hormone positive patients. With improvements in imaging, pathologic review, and treatment techniques in the modern era, combined with new information regarding tumor biology, the management of DCIS is rapidly evolving. A multidisciplinary approach to treatment is now more important than ever, with a shift towards de-escalating therapy to reduce treatment related toxicity. This review focuses on nuances of clinical management of DCIS in the modern era, highlighting key differences between DCIS as compared to invasive breast cancer. The American Cancer Society (ACS) currently recommends beginning screening with annual mammograms for women age 45, with the option to start at age 40. As treatment of DCIS has not been shown to impact survival, the USPSTF has more conservative screening recommendations of biennial mammograms from age 50-74. Unlike invasive breast cancer, DCIS is almost exclusively diagnosed by mammographic detection, and lymph node evaluation is not recommended. Pathologic review of biopsy specimens should follow the guidelines of the College of American Pathologists. Surgical management options include breast conservation, mastectomy, or possibly nipple sparing mastectomy, with upfront sentinel lymph node evaluation in the case of mastectomy. Radiation therapy is generally recommended as a component of breast conserving therapy for patients with DCIS, though in some low risk patients, there is trial data to suggest that adjuvant radiation may be omitted. Techniques for minimizing radiation toxicity should always be emphasized. Endocrine therapy is offered to women with hormone positive DCIS who have undergone lumpectomy for risk reduction, and has the benefit of decreasing incidence of events in both the ipsilateral and contralateral breast. More recent studies have explored use of targeted treatments such as trastuzumab in DCIS for HER2 overexpression. Future directions include tailoring therapy based on patient characteristics and tumor biology. With so many different options for treatment, it is also critical to engage in a discussion with the patient to arrive at a treatment decision that balances patient preferences for disease control versus treatment toxicity, financial toxicity, cosmesis, and quality of life.

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3-/- mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

Reducing Breast Cancer-Related Lymphedema (BCRL) Through Prospective Surveillance Monitoring Using Bioimpedance Spectroscopy (BIS) and Patient Directed Self-Interventions.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a chronic progressive disease that results from breast cancer treatment and nodal surgery. NCCN guidelines support baseline measurements with prospective assessment for early diagnosis and treatment. We sought to determine if baseline measurement with bioimpedance spectroscopy (BIS) and serial postoperative evaluations provide early detection amenable to conservative interventions that reduce BCRL. METHODS: Breast cancer patients with unilateral disease high-risk for BCRL from a single institution were evaluated from November 2014 to December 2017. High risk was defined as axillary lymph node dissection with radiation and/or taxane chemotherapy. Patients received preoperative baseline BIS measurements followed by postoperative measurements with at least two follow-ups. Patients with BIS results that were 2 standard deviations above baseline (10 + points) started home conservative interventions for 4-6 weeks. Postintervention measurements were taken to assess improvement. RESULT: A total of 146 patients high-risk for BCRL were included. Forty-nine patients (34%) developed early BCRL and started self-directed treatment. Forty patients (82%) had elevated BIS measurements return to normal baseline range. Nine (6%) patients had persistent BCRL requiring referral for advanced therapy. Patients with persistent BCRL had significant nodal burden on surgical pathology; eight (89%) had N2/N3 disease. Six (76%) with BCRL refractory to conservative measures died of their breast cancer. CONCLUSION: Our results demonstrated that early conservative intervention for breast cancer patients high risk for BCRL who were prospectively monitored by utilizing BIS significantly lowers rates of BCRL. These findings support early prospective screening and intervention for BCRL. Early detection with patient-directed interventions improves patient outcomes and decreases the risk of persistent BCRL.

The Use of Surgery and Radiotherapy as Treatment of Regional Nodes in Breast Cancer Patients.

Ipsilateral regional nodal status is an important independent prognostic factor for patients with breast cancer. Several decisions regarding local therapy are necessary for patients found to have pathologically involved lymph node(s). This article reviews the role of completion dissection and/or radiation therapy in patients found to have positive sentinel lymph node(s), taking into consideration use of mastectomy vs lumpectomy, tumor characteristics, tumor biology, plans for systemic therapy, and patient preferences. Published literature and current guidelines are reviewed, with emphasis on controversial topics such as regional nodal and postmastectomy radiation therapy for patients with one to three positive nodes. Choice of field design in patients undergoing radiation therapy will also be highlighted. Unique clinical situations such as locoregional treatment in patients receiving neoadjuvant chemotherapy and the emerging role of tumor biology and molecular assays in local therapy decision making will also be discussed.

Care delivery and compensation system changes: a case study of organizational readiness within a large dental care practice organization in the United States.

BACKGROUND: Dental care delivery systems in the United States are consolidating and large practice organizations are becoming more common. At the same time, greater accountability for addressing disparities in access to care is being demanded when public funds are used to pay for care. As change occurs within these new practice structures, attempts to implement change in the delivery system may be hampered by failure to understand the organizational climate or fail to prepare employees to accommodate new goals or processes. Studies of organizational behavior within oral health care are sparse and have not addressed consolidation of current delivery systems. The objective of this case study was to assess organizational readiness for implementing change in a large dental care organization consisting of staff model clinics and affiliated dental practices and test associations of readiness with workforce characteristics and work environment. METHODS: A dental care organization implemented a multifaceted quality improvement program, called PREDICT, in which community-based mobile and clinic-based dental services were integrated and the team compensated based in part on meeting performance targets. Dental care providers and supporting staff members (N = 181) were surveyed before program implementation and organizational readiness for implementing change (ORIC) was assessed by two 5-point scales: change commitment and efficacy. RESULTS: Providers and staff demonstrated high organizational readiness for change. Median change commitment was 3.8 (Interquartile range [IQR]: 3.3-4.3) and change efficacy was 3.8 (IQR: 3.0-4.2). In the adjusted regression model, change commitment was associated with organizational climate, support for methods to arrest tooth decay and was inversely related to office chaos. Change efficacy was associated with organizational climate, support for the company's mission and was inversely related to burnout. Each unit increase in the organizational climate scale predicted 0.45 and 0.8-unit increases in change commitment and change efficacy. CONCLUSIONS: The survey identified positive readiness for change and highlighted weaknesses that are important cautions for this organization and others initiating change. Future studies will examine how organizational readiness to change, workforce characteristics and work environment influenced successful implementation within this organization.

The α11 integrin mediates fibroblast-extracellular matrix-cardiomyocyte interactions in health and disease.

Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11ß1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-ß. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11(-/-); C57BL/6 background) treated with STZ compared with STZ-treated wild-type mice (P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated α11(-/-) mice, as shown by the decreased minimum rate of pressure change and prolonged time constant of relaxation in association with increased end-diastolic pressure (all P < 0.05 compared with wild-type mice). Accordingly, we examined the phenotype of untreated α11(-/-) mice, which demonstrated a reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 compared with wild-type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap-junction development. Overall, deletion of the α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, α11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast-cardiomyocyte and the ECM.

An experimental manipulation of social comparison in social anxiety.

Negative self-appraisal is thought to maintain social anxiety particularly when comparing oneself to others. Work on social comparison suggests that gender may moderate the effects of social comparison in social anxiety. Self-appraisals of the desirability of one's personality may be more important to women, whereas self-appraisal of signs of anxiety may be more important to men. Within each gender, those with high social anxiety are expected to report more negative self-appraisal when comparing themselves to someone else described as high achieving. This study is the first we are aware of that examined gender-based interactive effects after a social comparison manipulation. Participants read a bogus profile of a fellow student's adjustment to college. They were randomly assigned to read a profile suggesting that the fellow student was "high achieving" or more normative in his/her achievements. When comparing to a "high achieving" individual, men with high social anxiety reported the most negative self-appraisals of their signs of anxiety. In addition, greater social anxiety was associated with a poorer self-appraisal of personality only among men. The implications of the findings for conceptualizing the role of social comparison in social anxiety are discussed.

Interplay of Oncoplastic Reconstruction and Adjuvant Radiation Therapy in Breast Cancer.

Purpose: Oncoplastic breast surgery (OBS) combines breast cancer tumor removal with the cosmetic benefits of plastic surgery at the time of breast-conserving surgery. Potential advantages of OBS include wider surgical margins around the tumor bed, while the natural shape and appearance of the breast are maintained more than standard lumpectomy procedures. However, limited information is available regarding the potential effect on adjuvant radiation treatment planning. Materials and Methods: Women with localized breast cancer undergoing lumpectomy with immediate OBS and adjuvant radiation therapy between 2014 and 2019 were reviewed. OBS was performed using volume displacement techniques and patients received whole-breast irradiation with 3-dimensional conformal radiation therapy. Results: Volume of additional ipsilateral breast tissue removed during OBS ranged from 21 to 2086 cm3 (median, 304 cm3), 29% of patients had >500 cm3 of tissue removed. Surgical margins were positive in 12.5% and were not affected by volume of breast tissue removed (445 vs 439 cm3). Patients with surgical clips more often received a lumpectomy bed boost (75.9% vs 50.0%), boost volumes were on average 157 cm3 with clips versus 205 cm3 without clips. Mean V105 was comparable in patients with >500 cm3 tissue removed and irradiated breast volume >1000 cm3, while higher absolute volumes were found in patients with >26 cm posterior separation (58.0 cm3 vs 102.7 cm3; P = .07). No meaningful difference was observed in Dmax or radiation coverage (95% of the volume receiving 95% of the prescription dose) for patients with >26 cm posterior separation, >500 cm3 of breast tissue removed, or irradiated breast volume >1000 cm3. Conclusions: Radiation dosimetry plans for patients undergoing oncoplastic surgery were acceptable and no significant radiation or surgical advantage was gained in patients with more tissue removed. Our study stresses the importance of clear communication between surgeons and radiation oncologists about sufficient marking of the lumpectomy cavity, using practices that minimize the need for re-excisions and minimize lumpectomy cavity disruption during rearrangement.

Oncoplastic Reconstruction in the Setting of Prior Cosmetic Augmentation.

BACKGROUND: This study explores the surgical management and reconstruction options for augmented breasts in the context of breast conservation therapy (BCT) for breast cancer. We hypothesized that there would be no difference in the rates of complications, revisions, or patient satisfaction in patients who maintained their breast augmentation versus those that had their implants removed in the context of BCT. METHODS: We conducted a retrospective review of 142 patients who underwent BCT at a single center from March 2016 to March 2022. The study included patients who had a preexistent cosmetic augmentation at the time of breast cancer diagnosis and BCT. Patient demographics, clinical and treatment characteristics, breast implant details, reconstructive technique, complications, and revisions were recorded. Patient-reported outcomes were assessed using the BREAST-Q Breast-Conserving Therapy module. RESULTS: Ninety-three (65.5%) patients chose to maintain their implants, while 49 (34.5%) elected to have them removed during BCT. Patients with submuscular implants were more likely to maintain their implants. Oncoplastic mastopexy was associated with higher complication rates, particularly in patients opting for implant downsizing. However, multivariate logistic regression did not identify implant management strategy as an independent predictor for complications or revisions. Surgical site infection was the only predictor of implant explantation. Patient-reported outcomes did not differ significantly between the different implant management cohorts. CONCLUSIONS: This study demonstrates that maintaining breast implants during BCT does not increase the risk of complications or revisions. Overall, BCT in augmented women was found to be a safe approach, with high patient satisfaction.

Mixed-methods examination of attitudes and behaviors related to COVID-19 vaccines among parents of children with autism and autistic adults.

Increased risks associated with Coronavirus disease 2019 (COVID-19) among individuals with autism spectrum disorder (ASD) combined with previous reports of heightened vaccine hesitancy among parents of children with ASD indicate the need for a better understanding of attitudes and behaviors related to COVID-19 vaccines among the ASD community. This study is the first to our knowledge to use a mixed-methods approach to understand attitudes toward COVID-19 vaccines among parents of children with ASD and autistic adults. Participants were 135 members of the ASD community residing in the state of Arizona (99 parents of children with ASD and 36 autistic adults) who responded to the third (Spring 2021) and fourth (Summer 2021) time points of a larger longitudinal online survey. Quantitative findings indicated that autistic adults had slightly more favorable attitudes toward COVID-19 vaccines than parents, and attitudes in both subsamples became more positive over time. However, both parents and autistic adults reported COVID-19 vaccine uptake that was consistent with or better than the general population at both time points. Thematic analysis of responses to open-ended questions identified five themes that characterized factors that contributed to participants' decisions about COVID-19 vaccinations, including: (1) Desiring a Return to Normalcy, (2) Protection of Self and Others, (3) Previous Experience with COVID-19 (4) Science and Medical Professionals,and (5) Skepticism Regarding Safety, Effectiveness, and Need. Current findings combined with emerging literature paint a relatively optimistic picture about COVID-19 vaccine acceptance in the ASD community.

Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement.

BACKGROUND: Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST. STUDY DESIGN: We conducted a single-institution, retrospective study of 521 patients with cN2-3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan-Meier analyses were performed. RESULTS: The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor-positive (HR+)/HER2-negative tumors (HER2-; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008). CONCLUSIONS: In a high-risk cohort of patients with cN2-3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2-3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.

Intrathecal delivery of a bicistronic AAV9 vector expressing ß-hexosaminidase A corrects Sandhoff disease in a murine model: A dosage study.

The pathological accumulation of GM2 ganglioside associated with Tay-Sachs disease (TSD) and Sandhoff disease (SD) occurs in individuals who possess mutant forms of the heterodimer ß-hexosaminidase A (Hex A) because of mutation of the HEXA and HEXB genes, respectively. With a lack of approved therapies, patients experience rapid neurological decline resulting in early death. A novel bicistronic vector carrying both HEXA and HEXB previously demonstrated promising results in mouse models of SD following neonatal intravenous administration, including significant reduction in GM2 accumulation, increased levels of Hex A, and a 2-fold extension of survival. The aim of the present study was to identify an optimal dose of the bicistronic vector in 6-week-old SD mice by an intrathecal route of administration along with transient immunosuppression, to inform possible clinical translation. Three doses of the bicistronic vector were tested: 2.5e11, 1.25e11, and 0.625e11 vector genomes per mouse. The highest dose provided the greatest increase in biochemical and behavioral parameters, such that treated mice lived to a median age of 56 weeks (>3 times the lifespan of the SD controls). These results have direct implications in deciding a human equivalent dose for TSD/SD and have informed the approval of a clinical trial application (NCT04798235).