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PurposeSpatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.Methods and materialsPrimary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.ResultsClinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.ConclusionsThis consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

BackgroundSpinal cord dose limits are critically important for the safe practice of spine stereotactic body radiotherapy (SBRT). However, the effect of inherent spinal cord motion on cord dose in SBRT is unknown.ObjectiveTo assess the effects of cord motion on spinal cord dose in SBRT.MethodsDynamic balanced fast field echo (BFFE) magnetic resonance imaging (MRI) was obtained in 21 spine metastasis patients treated with SBRT. Planning computed tomography (CT), conventional static T2-weighted MRI, BFFE MRI, and dose planning data were coregistered. Spinal cord from the dynamic BFFE images (corddyn) was compared with the T2-weighted MRI (cordstat) to analyze motion of corddyn beyond the cordstat (Dice coefficient, Jaccard index), and beyond cordstat with added planning organ at risk volume (PRV) margins. Cord dose was compared between cordstat, and corddyn (Wilcoxon signed-rank test).ResultsDice coefficient (0.70-0.95, median 0.87) and Jaccard index (0.54-0.90, median 0.77) demonstrated motion of corddyn beyond cordstat. In 62% of the patients (13/21), the dose to corddyn exceeded that of cordstat by 0.6% to 13.8% (median 4.3%). The corddyn spatially excursed outside the 1-mm PRV margin of cordstat in 9 patients (43%); among these dose to corddyn exceeded dose to cordstat >+ 1-mm PRV margin in 78% of the patients (7/9). Corddyn did not excurse outside the 1.5-mm or 2-mm PRV cord cordstat margin.ConclusionSpinal cord motion may contribute to increases in radiation dose to the cord from SBRT for spine metastasis. A PRV margin of at least 1.5 to 2 mm surrounding the cord should be strongly considered to account for inherent spinal cord motion.

Purpose: Fathers play a critical but underresearched role in their children's cognitive and linguistic development. Focusing on two-parent families with a mother and a father, the present longitudinal study explores the amount of paternal input infants hear during the first 2 years of life, how this input changes over time, and how it relates to child volubility. We devote special attention to parentese, a near-universal style of infant-directed speech, distinguished by its higher pitch, slower tempo, and exaggerated intonation. Method: We examined the daylong recordings of the same 23 infants at ages 6, 10, 14, 18, and 24 months, given English-speaking families. The infants were recorded in the presence of their parents (mother-father dyads), who were predominantly White and ranged from mid to high socioeconomic status (SES). We analyzed the effects of parent gender and child age on adult word counts and parentese, as well as the effects of maternal and paternal word counts and parentese on child vocalizations. Results: On average, the infants were exposed to 46.8% fewer words and 51.9% less parentese from fathers than from mothers, even though paternal parentese grew at a 2.8-times faster rate as the infants aged. An asymmetry emerged where maternal word counts and paternal parentese predicted child vocalizations, but paternal word counts and maternal parentese did not. Conclusions: While infants may hear less input from their fathers than their mothers in predominantly White, mid-to-high SES, English-speaking households, paternal parentese still plays a unique role in their linguistic development. Future research on sources of variability in child language outcomes should thus control for parental differences since parents' language can differ substantially and differentially predict child language.

Purpose: Fathers play a critical but underresearched role in their children's cognitive and linguistic development. Focusing on two-parent families with a mother and a father, the present longitudinal study explores the amount of paternal input infants hear during the first 2 years of life, how this input changes over time, and how it relates to child volubility. We devote special attention to parentese, a near-universal style of infant-directed speech, distinguished by its higher pitch, slower tempo, and exaggerated intonation. Method: We examined the daylong recordings of the same 23 infants at ages 6, 10, 14, 18, and 24 months, given English-speaking families. The infants were recorded in the presence of their parents (mother-father dyads), who were predominantly White and ranged from mid to high socioeconomic status (SES). We analyzed the effects of parent gender and child age on adult word counts and parentese, as well as the effects of maternal and paternal word counts and parentese on child vocalizations. Results: On average, the infants were exposed to 46.8% fewer words and 51.9% less parentese from fathers than from mothers, even though paternal parentese grew at a 2.8-times faster rate as the infants aged. An asymmetry emerged where maternal word counts and paternal parentese predicted child vocalizations, but paternal word counts and maternal parentese did not. Conclusions: While infants may hear less input from their fathers than their mothers in predominantly White, mid-to-high SES, English-speaking households, paternal parentese still plays a unique role in their linguistic development. Future research on sources of variability in child language outcomes should thus control for parental differences since parents' language can differ substantially and differentially predict child language., Sociocultural frameworks have long emphasized child development as a socially mediated process, in which caregivers scaffold their children's cognitive and linguistic development through social interactions (e.g., Bruner, 1981; Kuhl, 2007, [...]

OBJECTIVE:To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS:AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P

BackgroundHigh-risk components of brain arteriovenous malformations (BAVMs) can be targeted to reduce the risk of lesion rupture.ObjectiveTo evaluate targeted embolization of aneurysms against other means of treatment with a case-control analysis; we previously investigated this approach associated with BAVMs.MethodsRetrospective analysis of patients with BAVMs was performed, identifying patients treated with intention to occlude only an aneurysm associated with a BAVM. For each targeted aneurysm embolization (TAE) patient identified, 4 control patients were randomly selected, controlling for rupture status, age, and Spetzler-Martin plus Lawton-Young supplemental score. Analysis was performed to compare rates of adverse events (hemorrhage, new seizure, and death) between the 2 groups.ResultsThirty-two patients met inclusion criteria, and 128 control patients were identified, out of 1103 patients treated during the study period. Thirty-four adverse events occurred (15 ruptures, 15 new seizures, and 11 deaths) during the follow-up period (mean 1157 d for the TAE cohort and 1036 d for the non-TAE cohort). Statistically lower associations were noted for the TAE group for any adverse event (hazard ratio 0.28, P = .037) and the composite outcome of hemorrhage or new seizure (hazard ratio 0.20, P = .029).ConclusionFor BAVMs at high risk for surgical resection, TAE can be performed safely and effectively. Patients treated with TAE had better outcomes than matched patients undergoing other combinations of treatment. TAE can be considered for BAVMs with high operative risk prior to radiosurgery or when no other treatment options are available.

Little is known about the prognostic significance of specific characteristics of magnetic resonance imaging (MRI) measured plaque in the superficial femoral artery (SFA). Associations of MRI-measured plaque quantity, lumen area, and plaque composition in the SFA with subsequent mobility loss were studied in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 1.00 were identified from Chicago medical centers and underwent direct visualization of atherosclerotic plaque in the SFA using MRI. Participants were followed annually for up to 4 years. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance among participants without mobility impairment at baseline. Analyses adjusted for age, sex, race, comorbidities, ABI, physical activity, and other confounders. Of 308 PAD participants without baseline mobility impairment, 100 (32.5%) developed mobility loss during follow-up. Compared to the lowest mean plaque area tertile at baseline, participants in the highest (worst) plaque area tertile had a higher rate of mobility loss (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.14-3.79, p = 0.018). Compared to the highest mean lumen area tertile, the smallest (worst) mean lumen area tertile was associated with greater mobility loss (HR = 2.18, 95% CI = 1.20-3.96, p = 0.011). Neither lipid rich necrotic core nor calcium in the SFA were associated with mobility loss. In conclusion, greater plaque quantity and smaller lumen area in the proximal SFA, but not lipid rich necrotic core or calcium, were associated with higher mobility loss in people with PAD.

ObjectivesThe aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic cardiovascular event rates.BackgroundLRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries.MethodsParticipants with ankle-brachial index (ABI) values 0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke.ConclusionsAmong patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events.